Journal articles
Jones SE, van Hees VT, Mazzotti DR, Marques-Vidal P, Sabia S, van der Spek A, Dashti HS, Engmann J, Kocevska D, Tyrrell J, et al (In Press). Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour.
Nature CommunicationsAbstract:
Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour
Sleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P
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Wright C, Tuke M, Frayling T, Weedon M, Murray A, Tyrrell J, Ruth K, Beaumont R, Wood A (In Press). Large copy number variants in UK Biobank caused by clonal haematopoiesis may confound penetrance estimates. American Journal of Human Genetics
Hawkes G, Beaumont RN, Tyrrell J, Power GM, Wood A, Laakso M, Fernandes Silva L, Boehnke M, Yin X, Richardson TG, et al (2023). Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood.
Diabetologia,
66(8), 1472-1480.
Abstract:
Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood.
AIMS/HYPOTHESIS: Determining how high BMI at different time points influences the risk of developing type 2 diabetes and affects insulin secretion and insulin sensitivity is critical. METHODS: By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation. We performed two-sample MR using external studies of type 2 diabetes, and oral and intravenous measures of insulin secretion and sensitivity. RESULTS: We found that a childhood BMI that was one standard deviation (1.97 kg/m2) higher than the mean, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including increased insulin sensitivity index (β=0.15; 95% CI 0.067, 0.225; p=2.79×10-4) and reduced fasting glucose levels (β=-0.053; 95% CI -0.089, -0.017; p=4.31×10-3). However, there was little to no evidence of a direct protective effect on type 2 diabetes (OR 0.94; 95% CI 0.85, 1.04; p=0.228) independently of genetic liability to adulthood BMI. CONCLUSIONS/INTERPRETATION: Our results provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty regarding the biological pathway of these effects and the limitations of this type of study.
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Williamson A, Norris DM, Yin X, Broadaway KA, Moxley AH, Vadlamudi S, Wilson EP, Jackson AU, Ahuja V, Andersen MK, et al (2023). Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.
Nat Genet,
55(6), 973-983.
Abstract:
Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.
Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P
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Liu J, Richmond RC, Bowden J, Barry C, Dashti HS, Daghlas I, Lane JM, Jones SE, Wood AR, Frayling TM, et al (2022). Assessing the Causal Role of Sleep Traits on Glycated Hemoglobin: a Mendelian Randomization Study.
Diabetes Care,
45(4), 772-781.
Abstract:
Assessing the Causal Role of Sleep Traits on Glycated Hemoglobin: a Mendelian Randomization Study.
OBJECTIVE: to examine the effects of sleep traits on glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS: This study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e. insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female). RESULTS: Across MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA1c (MVR 0.05 SD units [95% CI 0.04-0.06]; 1SMR 0.52 [0.42-0.63]; 2SMR 0.24 [0.11-0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect. CONCLUSIONS: Our results suggest that frequent insomnia symptoms cause higher HbA1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes.
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Murphy N, Song M, Papadimitriou N, Carreras-Torres R, Langenberg C, Martin RM, Tsilidis KK, Barroso I, Chen J, Frayling TM, et al (2022). Associations Between Glycemic Traits and Colorectal Cancer: a Mendelian Randomization Analysis.
J Natl Cancer Inst,
114(5), 740-752.
Abstract:
Associations Between Glycemic Traits and Colorectal Cancer: a Mendelian Randomization Analysis.
BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS: in inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
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Martin S, Tyrrell J, Thomas EL, Bown MJ, Wood AR, Beaumont RN, Tsoi LC, Stuart PE, Elder JT, Law P, et al (2022). Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation.
eLife,
11Abstract:
Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation
Background:Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases.Methods:We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically ‘favourable adiposity’ (FA) and ‘unfavourable adiposity’ (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases.Results:MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism.Conclusions:Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy.Funding:Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.
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Hayes BL, Robinson T, Kar S, Ruth KS, Tsilidis KK, Frayling T, Murray A, Martin RM, Lawlor DA, Richmond RC, et al (2022). Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? a Mendelian randomization study.
PLoS Genet,
18(1).
Abstract:
Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? a Mendelian randomization study.
Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p
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Harlow CE, Gandawijaya J, Bamford RA, Martin E-R, Wood AR, van der Most PJ, Tanaka T, Leonard HL, Etheridge AS, Innocenti F, et al (2022). Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.
Am J Hum Genet,
109(9), 1638-1652.
Abstract:
Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p
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Patel KA, Burman S, Laver TW, Hattersley AT, Frayling TM, Weedon MN (2022). PLIN1 Haploinsufficiency Causes a Favorable Metabolic Profile.
J Clin Endocrinol Metab,
107(6), e2318-e2323.
Abstract:
PLIN1 Haploinsufficiency Causes a Favorable Metabolic Profile.
CONTEXT: PLIN1 encodes perilipin-1, which coats lipid droplets in adipocytes and is involved in droplet formation, triglyceride storage, and lipolysis. Rare PLIN1 frameshift variants that extend the translated protein have been described to cause lipodystrophy. OBJECTIVE: This work aimed to test whether PLIN1 protein-truncating variants (PTVs) cause lipodystrophy in a large population-based cohort. METHODS: We identified individuals with PLIN1 PTVs in individuals with exome data in the UK Biobank. We performed gene-burden testing for individuals with PLIN1 PTVs. We replicated the associations using data from the T2D Knowledge portal. We performed a phenome-wide association study using publicly available association statistics. A total of 362 791 individuals in the UK Biobank, a population-based cohort, and 43 125 individuals in the T2D Knowledge portal, a type 2 diabetes (T2D) case-control study, were included in the analyses. Main outcome measures included 22 diseases and traits relevant to lipodystrophy. RESULTS: the 735 individuals with PLIN1 PTVs had a favorable metabolic profile. These individuals had increased high-density lipoprotein cholesterol (0.12 mmol/L; 95% CI, 0.09 to 0.14, P
=
2
×
10-18), reduced triglycerides (-0.22 mmol/L; 95% CI, -0.29 to -0.14, P
=
3
×
10-11), reduced waist-to-hip ratio (-0.02; 95% CI, -0.02 to -0.01, P
=
9
×
10-12), and reduced systolic blood pressure (-1.67 mm Hg; 95% CI, -3.25 to -0.09, P
=
.05). These associations were consistent in the smaller T2D Knowledge portal cohort. In the UK Biobank, PLIN1 PTVs were associated with reduced risk of myocardial infarction (odds ratio [OR]
=
0.59; 95% CI, 0.35 to 0.93, P
=
.02) and hypertension (OR
=
0.85; 95% CI, 0.73 to 0.98, P
=
.03), but not T2D (OR
=
0.99; 95% CI, 0.63-1.51, P
=
.99). CONCLUSION: Our study suggests that PLIN1 haploinsufficiency causes a favorable metabolic profile and may protect against cardiovascular disease.
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Porcu E, Sadler MC, Lepik K, Auwerx C, Wood AR, Weihs A, Sleiman MSB, Ribeiro DM, Bandinelli S, Tanaka T, et al (2021). Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome.
Nat Commun,
12(1).
Abstract:
Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome.
Comparing transcript levels between healthy and diseased individuals allows the identification of differentially expressed genes, which may be causes, consequences or mere correlates of the disease under scrutiny. We propose a method to decompose the observational correlation between gene expression and phenotypes driven by confounders, forward- and reverse causal effects. The bi-directional causal effects between gene expression and complex traits are obtained by Mendelian Randomization integrating summary-level data from GWAS and whole-blood eQTLs. Applying this approach to complex traits reveals that forward effects have negligible contribution. For example, BMI- and triglycerides-gene expression correlation coefficients robustly correlate with trait-to-expression causal effects (rBMI = 0.11, PBMI = 2.0 × 10-51 and rTG = 0.13, PTG = 1.1 × 10-68), but not detectably with expression-to-trait effects. Our results demonstrate that studies comparing the transcriptome of diseased and healthy subjects are more prone to reveal disease-induced gene expression changes rather than disease causing ones.
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Tyrrell J, Zheng J, Beaumont R, Hinton K, Richardson TG, Wood AR, Davey Smith G, Frayling TM, Tilling K (2021). Genetic predictors of participation in optional components of UK Biobank.
Nat Commun,
12(1).
Abstract:
Genetic predictors of participation in optional components of UK Biobank.
Large studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components (P
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Vosa U, Claringbould A, Westra H-J, Bonder MJ, Deelen P, Zeng B, Kirsten H, Saha A, Kreuzhuber R, Yazar S, et al (2021). Large-scale <i>cis</i>- and <i>trans</i>-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.
NATURE GENETICS,
53(9), 1300-+.
Author URL.
Power GM, Tyrrell J, Frayling TM, Davey Smith G, Richardson TG (2021). Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences end Points from Across the Cardiovascular Disease Spectrum Through Adult Body Size.
J Am Heart Assoc,
10(17).
Abstract:
Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences end Points from Across the Cardiovascular Disease Spectrum Through Adult Body Size.
Background Obesity is associated with long-term health consequences including cardiovascular disease. Separating the independent effects of childhood and adulthood obesity on cardiovascular disease risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results This study used 2-sample univariable and multivariable Mendelian randomization to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the cardiovascular disease disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease, and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable Mendelian randomization, suggesting that childhood body size indirectly increases risk of these 8 disease outcomes via the pathway involving adult body size. Conclusions These findings suggest that the effect of genetically predicted childhood body size on the cardiovascular disease outcomes analyzed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where, if ever, the detrimental impact of obesity initiated in early life begins to become immutable.
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Lagou V, Mägi R, Hottenga J-J, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, et al (2021). Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.
Nat Commun,
12(1).
Author URL.
Lagou V, Mägi R, Hottenga J-J, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, et al (2021). Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.
Nat Commun,
12(1).
Abstract:
Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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Weedon MN, Wright CF, Patel KA, Frayling TM (2021). Unreliability of genotyping arrays for detecting very rare variants in human genetic studies: Example from a recent study of MC4R. Cell, 184(7).
Casanova F, Wood AR, Yaghootkar H, Beaumont RN, Jones SE, Gooding KM, Aizawa K, Strain WD, Hattersley AT, Khan F, et al (2020). A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.
Diabetes,
69(5), 1072-1082.
Abstract:
A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.
Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.
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Green HD, Jones A, Evans JP, Wood AR, Beaumont RN, Tyrrell J, Frayling TM, Smith C, Weedon MN (2020). A genome wide association study of frozen shoulder identifies a common variant of <i>WNT7B</i> and diabetes as causal risk factors.
Abstract:
A genome wide association study of frozen shoulder identifies a common variant of WNT7B and diabetes as causal risk factors
AbstractFrozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes.We performed a genome wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 2064 cases identified from ICD-10 codes. We used data from FinnGen for replication. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder.We identified a single genome-wide significant locus (lead SNP rs62228062; OR=1.34 [1.28-1.41], p=2×10−16) that contained WNT7B. A recent transcriptome study identified WNT7B as amongst the most enriched transcripts in anterior capsule tissue in patients undergoing arthroscopic capsulotomy surgery for frozen shoulder suggesting WNT7B as a potential causal gene at the locus. The lead SNP was also strongly associated with Dupuytren’s contracture (OR=2.61 [2.50, 2.72], p<1×10−100). The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR=1.04 [1.02-1.07], p=6×10−5). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects.We have identified the first genetic variant associated with frozen shoulder. WNT7B is a potential causal gene at the locus. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.
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Thompson WD, Beaumont RN, Kuang A, Warrington NM, Ji Y, Tyrrell J, Wood AR, Scholtens D, Knight BA, Evans DM, et al (2020). Fetal alleles predisposing to metabolically favourable adiposity are associated with higher birth weight.
Abstract:
Fetal alleles predisposing to metabolically favourable adiposity are associated with higher birth weight
AbstractBackgroundHigher birth weight is associated with higher adult body mass index (BMI). If genetic variants can be identified with alleles that predispose to both greater fetal growth and to greater adult adiposity, such shared genetic effects might indicate biological processes important in the early patterning of adiposity. However, variants identified in genome-wide association studies of adult BMI have overall been only weakly associated with birth weight. Genetic variants have recently been identified where one allele is associated with higher adult body fat percentage, but lower risk of metabolic disease, likely due to a favourable body fat distribution. The effect of these adult metabolically favourable adiposity alleles on an individual’s own birth weight is unknown.AimWe aimed to test the effect on birth weight of a fetal genetic predisposition to higher metabolically favourable adult adiposity and to compare this with the effects of a fetal genetic predisposition to higher adult BMI. We also aimed to examine the effects of a genetic predisposition to higher metabolically favourable adult adiposity or BMI on other birth anthropometric traits (length, ponderal index, head circumference and skinfold thickness) and on cord-blood insulin, leptin and adiponectin.MethodsWe used published GWAS data from up to 406,063 individuals to estimate the fetal effects on birth weight of alleles that are robustly associated with higher metabolically favourable adult adiposity or BMI. We additionally used 9,350 mother-child pairs from four cohorts to test the effects of the same alleles on other birth anthropometric traits and cord-blood markers. In all analyses, we adjusted for potential confounding due to the maternal genotype. We used inverse-variance weighted meta-analyses to combine summary data across SNPs.ResultsFetal genetic predisposition to higher metabolically favourable adult adiposity was associated with higher birth weight (10 grams (95% CI: 7 to 13) higher mean birth weight per 1 SD pooled “genetic score”). Fetal genetic predisposition to higher adult BMI was also associated with higher birth weight, but with a smaller magnitude of effect (4 grams (95% CI: 0 to 8) higher mean birth weight per 1 SD pooled “genetic score”) and with higher heterogeneity across SNPs. Effects on other birth anthropometric outcomes were consistent with the effect on birth weight but with wider confidence intervals. There was no strong evidence for an effect on cord-blood markers.ConclusionsSome genetic variants previously linked to adult adiposity influence birth weight. Alleles that predispose to higher metabolically favourable adult adiposity collectively have a stronger effect on birth weight than those predisposing to higher BMI. This suggests that the early accumulation of a metabolically favourable fat distribution might underlie part of the observed association between higher birth weight and higher adult BMI. Larger samples are needed to clarify the effects on other birth anthropometric measures and cord-blood markers.
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Yaghootkar H, Zhang Y, Spracklen CN, Karaderi T, Huang LO, Bradfield J, Schurmann C, Fine RS, Preuss MH, Kutalik Z, et al (2020). Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.
Diabetes,
69(12), 2806-2818.
Abstract:
Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.
Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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Author URL.
Green HD, Beaumont RN, Wood AR, Hamilton B, Jones SE, Goodhand JR, Kennedy NA, Ahmad T, Yaghootkar H, Weedon MN, et al (2020). Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.
International Journal of Epidemiology,
49(4), 1270-1281.
Abstract:
Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study
Abstract
.
. Background
. Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD.
.
.
. Methods
. We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist–hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption.
.
.
. Results
. Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference.
.
.
. Conclusions
. These results provide strong evidence that a higher waist–hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.
.
Abstract.
Thompson WD, Beaumont RN, Kuang A, Warrington NM, Ji Y, Tyrrell J, Wood AR, Scholtens D, Knight BA, Evans DM, et al (2020). Higher maternal adiposity reduces offspring birth weight if associated with a metabolically favourable profile.
Abstract:
Higher maternal adiposity reduces offspring birth weight if associated with a metabolically favourable profile
AbstractAims/HypothesisHigher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity coupled with a favourable metabolic profile, in a Mendelian Randomisation (MR) study comparing the effect of maternal “metabolically favourable adiposity” on offspring birth weight with the effect of maternal general adiposity (as indexed by BMI).MethodsTo test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birth weight, we performed two sample MR. We used variants identified in large genetic association studies as associated with either higher adiposity and a favourable metabolic profile, or higher BMI (N = 442,278 and N = 322,154 for metabolically favourable adiposity and BMI, respectively). We then used data from the same variants in a large genetic study of maternal genotype and offspring birth weight independent of fetal genetic effects (N = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total N = 9,323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birth weight and cord-blood biomarkers.ResultsHigher maternal adiposity with a favourable metabolic profile was associated with lower offspring birth weight (−94 (95% CI: −150 to −38) grams per 1 SD (6.5%) higher maternal metabolically favourable adiposity). By contrast, higher maternal BMI was associated with higher offspring birth weight (35 (95% CI: 16 to 53) grams per 1 SD (4 kg/m2) higher maternal BMI). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures and their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels whilst maternal BMI increases them.The effects on neonatal anthropometric traits were consistent with the overall effect on birth weight, but the smaller sample sizes for these analyses meant the effects were imprecisely estimated. We also found evidence to suggest that maternal metabolically favourable adiposity decreases cord-blood leptin whilst maternal BMI increases it.Conclusions/InterpretationOur results show that higher adiposity in mothers does not necessarily lead to higher offspring birth weight. Higher maternal adiposity can lead to lower offspring birth weight if accompanied by a favourable metabolic profile.Research in ContextWhat is already known about this subject?Studies in non-pregnant people with obesity suggest many people can have a “metabolically healthy” form of obesity, but effects in pregnancy and on offspring are not known.Multiple lines of evidence show that higher maternal BMI is causally associated with higher offspring birth weight, and that this may be mediated by the fetal insulin response to higher maternal gestational glucose.Recently, genetic variants have been identified, where one allele is associated with higher adiposity but lower risk of type II diabetes and favourable metabolic profile, including lower insulin and glucose levels, so called “metabolically favourable adiposity”; the mechanism is thought to be due to greater subcutaneous adipose storage capacity that leads to higher insulin sensitivity.What is the key question?What is the effect of maternal metabolically favourable adiposity on birth weight, and how does it compare with the effect of maternal BMI on birth weight?What are the new findings?Higher maternal adiposity can lead to lower, not higher birth weight, if it is also associated with a metabolically favourable profile; this contrasts with the effect of higher maternal general adiposity (BMI), on higher birth weight.Higher maternal metabolically favourable adiposity causes lower maternal fasting plasma glucose levels, most likely due to higher insulin sensitivity; in contrast higher maternal general adiposity leads to higher maternal fasting plasma glucose levels, most likely due to lower insulin sensitivity.How might this impact on clinical practice in the foreseeable future?Identifying ways of stratifying overweight and obese pregnant women into those with and without metabolically favourable adiposity could allow for targeted management to obtain healthy fetal growth and birth weight.
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Glastonbury CA, Pulit SL, Honecker J, Censin JC, Laber S, Yaghootkar H, Rahmioglu N, Pastel E, Kos K, Pitt A, et al (2020). Machine Learning based histology phenotyping to investigate the epidemiologic and genetic basis of adipocyte morphology and cardiometabolic traits. PLOS Computational Biology, 16(8), e1008044-e1008044.
Zeman AZJ, Milton F, Della Sala S, Dewar M, Frayling T, Gaddum J, Hattersley A, Heuerman-Williamson B, Jones K, Mackisack M, et al (2020). Phantasia - the psychological significance of lifelong visual imagery vividness extremes. Cortex, 130, 426-440.
Zeman A, Milton F, Della Sala S, Dewar M, Frayling T, Gaddum J, Hattersley A, Heuerman-Williamson B, Jones K, MacKisack M, et al (2020). Phantasia - the psychological significance of lifelong visual imagery vividness extremes.
Abstract:
Phantasia - the psychological significance of lifelong visual imagery vividness extremes
Visual imagery typically enables us to see absent items in the mind’s eye. It plays a role in memory, day-dreaming and creativity. Since coining the terms aphantasia and hyperphantasia to describe the absence and abundance of visual imagery, we have been contacted by many thousands of people with extreme imagery abilities. Questionnaire data from 2000 participants with aphantasia and 200 with hyperphantasia indicate that aphantasia is associated with scientific and mathematical occupations, whereas hyperphantasia is associated with ‘creative’ professions. Participants with aphantasia report an elevated rate of difficulty with face recognition and autobiographical memory, whereas participants with hyperphantasia report an elevated rate of synaesthesia. Around half those with aphantasia describe an absence of wakeful imagery in all sense modalities, while a majority dream visually. Aphantasia appears to run within families more often than would be expected by chance. Aphantasia and hyperphantasia appear to be widespread but neglected features of human experience with informative psychological associations.
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Sulc J, Mounier N, Günther F, Winkler T, Wood AR, Frayling TM, Heid IM, Robinson MR, Kutalik Z (2020). Quantification of the overall contribution of gene-environment interaction for obesity-related traits.
Nat Commun,
11(1).
Abstract:
Quantification of the overall contribution of gene-environment interaction for obesity-related traits.
The growing sample size of genome-wide association studies has facilitated the discovery of gene-environment interactions (GxE). Here we propose a maximum likelihood method to estimate the contribution of GxE to continuous traits taking into account all interacting environmental variables, without the need to measure any. Extensive simulations demonstrate that our method provides unbiased interaction estimates and excellent coverage. We also offer strategies to distinguish specific GxE from general scale effects. Applying our method to 32 traits in the UK Biobank reveals that while the genetic risk score (GRS) of 376 variants explains 5.2% of body mass index (BMI) variance, GRSxE explains an additional 1.9%. Nevertheless, this interaction holds for any variable with identical correlation to BMI as the GRS, hence may not be GRS-specific. Still, we observe that the global contribution of specific GRSxE to complex traits is substantial for nine obesity-related measures (including leg impedance and trunk fat-free mass).
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Author URL.
Ruth KS, Day FR, Tyrrell J, Thompson DJ, Wood AR, Mahajan A, Beaumont RN, Wittemans L, Martin S, Busch AS, et al (2020). Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine, 26(2), 252-258.
Casanova F, Tyrrell J, Beaumont RN, Ji Y, Jones SE, Hattersley AT, Weedon MN, Murray A, Shore AC, Frayling TM, et al (2019). A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.
Hum Mol Genet,
28(24), 4197-4207.
Abstract:
A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.
Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular-related disease. We performed a genome-wide association study of ACR using 437 027 individuals from the UK Biobank in the discovery phase, 54 527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P 0.8) coinciding with signals for at least 16 related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes-a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P ≤ 4 × 10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.
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Wright CF, West B, Tuke M, Jones SE, Patel K, Laver TW, Beaumont RN, Tyrrell J, Wood AR, Frayling TM, et al (2019). Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
American Journal of Human Genetics,
104(2), 275-286.
Abstract:
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
Abstract.
Lane JM, Jones SE, Dashti HS, Wood AR, Aragam KG, van Hees VT, Strand LB, Winsvold BS, Wang H, Bowden J, et al (2019). Biological and clinical insights from genetics of insomnia symptoms.
Nature GeneticsAbstract:
Biological and clinical insights from genetics of insomnia symptoms
Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n = 14,923 cases, 47,610 controls), physician-diagnosed insomnia in Partners Biobank (n = 2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms and subjective well-being.
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Howe LD, Kanayalal R, Beaumont RN, Davies AR, Frayling TM, Harrison S, Jones SE, Sassi F, Wood AR, Tyrrell J, et al (2019). Effects of body mass index on relationship status, social contact, and socioeconomic position: Mendelian Randomization study in UK Biobank.
Abstract:
Effects of body mass index on relationship status, social contact, and socioeconomic position: Mendelian Randomization study in UK Biobank
AbstractObjectiveTo assess whether body mass index (BMI) has a causal effect on social and socioeconomic factors, including whether both high and low BMI can be detrimental.DesignMendelian Randomization, using genetic variants for BMI to obtain unconfounded estimates, and non-linear Mendelian Randomization.SettingUK Biobank.Participants378,244 men and women of European ancestry, mean age 57 (SD 8 years).Main outcome measuresTownsend deprivation index, income, age completed full time education, degree level education, job class, employment status, cohabiting relationship status, participation in leisure and social activities, visits from friends and family, and having someone to confide in.ResultsHigher BMI was causally associated with higher deprivation, lower income, fewer years of education, lower odds of degree-level education and skilled employment. For example, a 1 SD higher genetically-determined BMI (4.8kg/m2 in UK Biobank) was associated with £1,660 less income per annum [95%CI: £950, £2,380]. Non-linear Mendelian Randomization provided evidence that both low BMI (bottom decile, <22kg/m2) and high BMI (top seven deciles, >24.6kg/m2) can increase deprivation and reduce income. In men only, higher BMI was related to lower participation in leisure and social activities. There was no evidence of causal effects of BMI on visits from friends and family or in having someone to confide in. Non-linear Mendelian Randomization analysis showed that low BMI (bottom three deciles, <23.5kg/m2) reduces the odds of cohabiting with a partner or spouse for men, whereas high BMI (top two deciles, >30.7kg/m2) reduces the odds of cohabitation with a partner or spouse for women.ConclusionsBMI affects social and socioeconomic outcomes, with both high and low BMI being detrimental for some measures of SEP. This suggests that in addition to health benefits, maintaining healthy ranges of BMI across the population could have benefits both for individuals and society.
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Budu-Aggrey A, Brumpton B, Tyrrell J, Watkins S, Modasli E, Celis-Morales C, Ferguson L, Vie G, Palmer T, Fritsche L, et al (2019). Evidence of a causal relationship between body mass index and psoriasis: a mendelian randomization study. PLoS Medicine
Alves AC, De Silva NMG, Karhunen V, Sovio U, Das S, Rob Taal H, Warrington NM, Lewin AM, Kaakinen M, Cousminer DL, et al (2019). GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.
Science Advances,
5(9).
Abstract:
GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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Ji Y, Yiorkas AM, Frau F, Mook-Kanamori D, Staiger H, Thomas EL, Atabaki-Pasdar N, Campbell A, Tyrrell J, Jones SE, et al (2019). Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.
Diabetes,
68(1), 207-219.
Abstract:
Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.
Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
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Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, Beaumont RN, Jeffries AR, Dashti HS, Hillsdon M, Ruth KS, et al (2019). Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.
Nature CommunicationsAbstract:
Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms
Using genome-wide data from 697,828 UK Biobank and 23andMe participants, we increase the number of identified loci associated with being a morning person, a behavioural indicator of a person’s underlying circadian rhythm, from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we demonstrate that the chronotype loci influence sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 minutes earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.
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Wang H, Lane JM, Jones SE, Dashti HS, Ollila HM, Wood AR, van Hees VT, Brumpton B, Winsvold BS, Kantojärvi K, et al (2019). Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.
Nature Communications,
10(1).
Abstract:
Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes
Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.
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Dashti HS, Jones SE, Wood AR, Lane JM, van Hees VT, Wang H, Rhodes JA, Song Y, Patel K, Anderson SG, et al (2019). Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
Nat Commun,
10(1).
Abstract:
Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration (p
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Richmond RC, Anderson EL, Dashti HS, Jones SE, Lane JM, Strand LB, Brumpton B, Rutter MK, Wood AR, Straif K, et al (2019). Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.
BMJ,
365Abstract:
Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.
OBJECTIVE: to examine whether sleep traits have a causal effect on risk of breast cancer. DESIGN: Mendelian randomisation study. SETTING: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study. PARTICIPANTS: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis. EXPOSURES: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits. MAIN OUTCOME MEASURE: Breast cancer diagnosis. RESULTS: in multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy. CONCLUSIONS: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.
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Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, et al (2019). Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Nat Genet,
51(5), 804-814.
Abstract:
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, Yengo L, Ferreira T, Marouli E, Ji Y, et al (2019). Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.
Hum Mol Genet,
28(1), 166-174.
Abstract:
Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.
More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
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Tuke MA, Ruth KS, Wood AR, Beaumont RN, Tyrrell J, Jones SE, Yaghootkar H, Turner CLS, Donohoe ME, Brooke AM, et al (2019). Mosaic Turner syndrome shows reduced penetrance in an adult population study.
Genet Med,
21(4), 877-886.
Abstract:
Mosaic Turner syndrome shows reduced penetrance in an adult population study.
PURPOSE: Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the penetrance has been overestimated. METHODS: We characterized the prevalence and phenotypic consequences of X chromosome aneuploidy in a population of 244,848 women over 40 years of age from UK Biobank, using single-nucleotide polymorphism (SNP) array data. RESULTS: We detected 30 women with 45,X; 186 with mosaic 45,X/46,XX; and 110 with 47,XXX. The prevalence of nonmosaic 45,X (12/100,000) and 47,XXX (45/100,000) was lower than expected, but was higher for mosaic 45,X/46,XX (76/100,000). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognized Turner syndrome phenotype, including short stature and primary amenorrhea. In contrast, women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. The phenotype of women with 47,XXX included taller stature (5.3 cm; SD = 5.52 cm; P = 5.8 × 10-20) and earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 × 10-14). CONCLUSION: Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.
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Tyrrell J, Mulugeta A, Wood AR, Zhou A, Beaumont RN, Tuke MA, Jones SE, Ruth KS, Yaghootkar H, Sharp S, et al (2019). Using genetics to understand the causal influence of higher BMI on depression.
Int J Epidemiol,
48(3), 834-848.
Abstract:
Using genetics to understand the causal influence of higher BMI on depression.
BACKGROUND: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. METHODS: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. RESULTS: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P
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Frayling TM (2018). A Common Allele in FGF21 Associated with Sugar Intake is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure. Cell Reports, 23(2), 327-336.
van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, Ladenvall C, Ziemek D, Fauman E, Robertson NR, et al (2018). A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects with Type 2 Diabetes.
Diabetes,
67(7), 1414-1427.
Abstract:
A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects with Type 2 Diabetes.
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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Flannick J, Fuchsberger C, Mahajan A, Teslovich TM, Agarwala V, Gaulton KJ, Caulkins L, Koesterer R, Ma C, Moutsianas L, et al (2018). Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.
Sci Data,
5Abstract:
Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.
This corrects the article DOI: 10.1038/sdata.2017.179.
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Author URL.
van Hees VT, Sabia S, Jones SE, Wood AR, Anderson KN, Kivimaki M, Frayling TM, Pack AI, Bucan M, Trenell MI, et al (2018). Estimating sleep parameters using an accelerometer without sleep diary.
SCIENTIFIC REPORTS,
8 Author URL.
Jun G, Manning A, Almeida M, Zawistowski M, Wood AR, Teslovich TM, Fuchsberger C, Feng S, Cingolani P, Gaulton KJ, et al (2018). Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.
Proc Natl Acad Sci U S A,
115(2), 379-384.
Abstract:
Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.
A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.
Abstract.
Author URL.
Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, Payne AJ, Steinthorsdottir V, Scott RA, Grarup N, et al (2018). Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.
Nat Genet,
50(11), 1505-1513.
Abstract:
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
Abstract.
Author URL.
Corbin LJ, Tan VY, Hughes DA, Wade KH, Paul DS, Tansey KE, Butcher F, Dudbridge F, Howson JM, Jallow MW, et al (2018). Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.
Nat Commun,
9(1).
Abstract:
Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference.
Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.
Abstract.
Author URL.
Nielsen JB, Fritsche LG, Zhou W, Teslovich TM, Holmen OL, Gustafsson S, Gabrielsen ME, Schmidt EM, Beaumont R, Wolford BN, et al (2018). Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development.
Am J Hum Genet,
102(1), 103-115.
Abstract:
Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development.
Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10-18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10-11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.
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Author URL.
Xue A, Wu Y, Zhu Z, Zhang F, Kemper KE, Zheng Z, Yengo L, Lloyd-Jones LR, Sidorenko J, Wu Y, et al (2018). Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.
Nature Communications,
9(1).
Abstract:
Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.
Abstract.
Wang H, Lane JM, Jones SE, Dashti HS, Ollila H, Wood AR, van Hees VT, Brumpton B, Winsvold BS, Kantojärvi K, et al (2018). Genome-wide association analysis of excessive daytime sleepiness identifies 42 loci that suggest phenotypic subgroups.
Abstract:
Genome-wide association analysis of excessive daytime sleepiness identifies 42 loci that suggest phenotypic subgroups
AbstractExcessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. We identified 42 loci for self-reported EDS in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirmed the aggregate effect of a genetic risk score of 42 SNPs on EDS in independent Scandinavian cohorts and on other sleep disorders (restless leg syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). Strong genetic correlations were also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing. EDS variants clustered into two predominant composite phenotypes - sleep propensity and sleep fragmentation - with the former showing stronger evidence for enriched expression in central nervous system tissues, suggesting two unique mechanistic pathways. Mendelian randomization analysis indicated that higher BMI is causally associated with EDS risk, but EDS does not appear to causally influence BMI.
Abstract.
Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, Geller F, Myhre R, Richmond RC, Paternoster L, et al (2018). Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
Hum Mol Genet,
27(4), 742-756.
Abstract:
Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P
Abstract.
Author URL.
Qi T, Wu Y, Zeng J, Zhang F, Xue A, Jiang L, Zhu Z, Kemper K, Yengo L, Zheng Z, et al (2018). Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood.
Nature Communications,
9(1).
Abstract:
Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b = 0.70 for cis-eQTLs and r ^ b = 0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.
Abstract.
Moore AZ, Ding J, Tuke MA, Wood AR, Bandinelli S, Frayling TM, Ferrucci L (2018). Influence of cell distribution and diabetes status on the association between mitochondrial DNA copy number and aging phenotypes in the InCHIANTI study.
Aging Cell,
17(1).
Abstract:
Influence of cell distribution and diabetes status on the association between mitochondrial DNA copy number and aging phenotypes in the InCHIANTI study.
Mitochondrial DNA copy number (mtDNA-CN) estimated in whole blood is a novel marker of mitochondrial mass and function that can be used in large population-based studies. Analyses that attempt to relate mtDNA-CN to specific aging phenotypes may be confounded by differences in the distribution of blood cell types across samples. Also, low or high mtDNA-CN may have a different meaning given the presence of diseases associated with mitochondrial damage. We evaluated the impact of blood cell type distribution and diabetes status on the association between mtDNA-CN and aging phenotypes, namely chronologic age, interleukin-6, hemoglobin, and all-cause mortality, among 672 participants of the InCHIANTI study. After accounting for white blood cell count, platelet count, and white blood cell proportions in multivariate models, associations of mtDNA-CN with age and interleukin-6 were no longer statistically significant. Evaluation of a statistical interaction by diabetes status suggested heterogeneity of effects in the analysis of mortality (P
Abstract.
Author URL.
Richmond RC, Anderson EL, Dashti HS, Jones SE, Lane JM, Strand LB, Brumpton B, Rutter M, Wood AR, Relton CL, et al (2018). Investigating causal relationships between sleep traits and risk of breast cancer: a Mendelian randomization study.
Abstract:
Investigating causal relationships between sleep traits and risk of breast cancer: a Mendelian randomization study
AbstractObjectiveTo examine whether sleep traits have a causal effect on risk of breast cancer.DesignMultivariable regression, one- and two-sample Mendelian randomization.SettingThe UK Biobank prospective cohort study and the Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.Participants156,848 women in the multivariable regression and one-sample Mendelian randomization analysis in UK Biobank (7,784 with a breast cancer diagnosis) and 122,977 breast cancer cases and 105,974 controls from BCAC in the two-sample Mendelian randomization analysis.ExposuresSelf-reported chronotype (morning/evening preference), insomnia symptoms and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.Main outcome measuresBreast cancer (prevalent and incident cases in UK Biobank, prevalent cases only in BCAC).ResultsIn multivariable regression analysis using data on breast cancer incidence in UK Biobank, morning preference was inversely associated with breast cancer (HR 0.95, 95% CI 0.93, 0.98 per category increase) while there was little evidence for an association with sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated sleep duration and 57 SNPs associated with insomnia symptoms, one-sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (HR 0.85, 95% 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two-sample MR using data from BCAC supported findings for a protective effect of morning preference (OR 0.88, 95% CI 0.82, 0.93 per category increase) and adverse effect of increased sleep duration (OR 1.19, 95% CI 1.02, 1.39 per hour increase) on breast cancer (both estrogen receptor positive and negative), while there was inconsistent evidence for insomnia symptoms. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.ConclusionsWe found consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of sleep duration on breast cancer risk.
Abstract.
Frayling TM, Stoneman CE (2018). Mendelian randomisation in type 2 diabetes and coronary artery disease.
Curr Opin Genet Dev,
50, 111-120.
Abstract:
Mendelian randomisation in type 2 diabetes and coronary artery disease.
Type 2 diabetes, coronary artery disease and hypertension are associated with anthropometric and biomarker traits, including waist-to-hip-ratio, body mass index and altered glucose and insulin levels. Clinical trials, for example of weight-loss interventions, show these factors are causal, but lifelong impact of subtle changes in body mass index and body fat distribution are less clear. The use of human genetics can quantify the causal effects of long-term exposure to subtle changes of modifiable risk factors. Mendelian randomisation (MR) uses human genetic variants associated with the risk factor to quantify the relationship between risk factor and disease outcome. The last two years have seen an increase in the number of MR studies investigating the relationship between anthropometric traits and metabolic diseases. This review provides an overview of these recent MR studies in relation to type 2 diabetes, coronary artery disease and hypertension. MR provides evidence for causal associations of waist-to-hip-ratio, body mass index and altered glucose levels with type 2 diabetes, coronary artery disease and hypertension.
Abstract.
Author URL.
Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, Frayling TM, Hirschhorn J, Yang J, Visscher PM, et al (2018). Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry.
Hum Mol Genet,
27(20), 3641-3649.
Abstract:
Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry.
Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ∼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N ∼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P
Abstract.
Author URL.
Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, et al (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Nat Genet,
50(1), 26-41.
Abstract:
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Abstract.
Author URL.
Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, et al (2018). Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Nat Genet,
50(5), 765-766.
Abstract:
Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.
Abstract.
Author URL.
Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, et al (2018). Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Nat Genet,
50(5), 766-767.
Abstract:
Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
Abstract.
Author URL.
Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR, Chu AY, Gan W, Kitajima H, Taliun D, Rayner NW, et al (2018). Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.
Nat Genet,
50(4), 559-571.
Abstract:
Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P
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Author URL.
Wood AR, Jonsson A, Jackson AU, Wang N, van Leewen N, Palmer ND, Kobes S, Deelen J, Boquete-Vilarino L, Paananen J, et al (2017). A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.
Diabetes,
66(8), 2296-2309.
Abstract:
A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants.
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
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Author URL.
Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M, Pervjakova N, Pers TH, Johnson AD, Eicher JD, et al (2017). An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.
Diabetes,
66(11), 2888-2902.
Abstract:
An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.
To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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Author URL.
Lepik K, Annilo T, Kukuškina V, eQTLGen Consortium, Kisand K, Kutalik Z, Peterson P, Peterson H (2017). C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis.
PLoS Comput Biol,
13(9).
Abstract:
C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis.
Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.
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Author URL.
Macé A, Tuke MA, Deelen P, Kristiansson K, Mattsson H, Nõukas M, Sapkota Y, Schick U, Porcu E, Rüeger S, et al (2017). CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.
Nat Commun,
8(1).
Abstract:
CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.
There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g. MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
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Author URL.
Song C, Burgess S, Eicher JD, O'Donnell CJ, Johnson AD, Huang J, Sabater-Lleal M, Asselbergs FW, Tregouet D, Shin SY, et al (2017). Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease.
Journal of the American Heart Association,
6(6).
Abstract:
Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease
Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
Abstract.
Graff M, Scott RA, Justice AE, Young KL, Feitosa MF, Barata L, Winkler TW, Chu AY, Mahajan A, Hadley D, et al (2017). Correction: Genome-wide physical activity interactions in adiposity - a meta-analysis of 200,452 adults.
PLoS Genet,
13(8).
Abstract:
Correction: Genome-wide physical activity interactions in adiposity - a meta-analysis of 200,452 adults.
[This corrects the article DOI: 10.1371/journal.pgen.1006528.].
Abstract.
Author URL.
Lotta LA, Gulati P, Day FR, Payne F, Ongen H, van de Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, et al (2017). Corrigendum: Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
Nat Genet,
49(2).
Author URL.
Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves AC, et al (2017). Exome-wide association study of plasma lipids in >300,000 individuals.
Nat Genet,
49(12), 1758-1766.
Abstract:
Exome-wide association study of plasma lipids in >300,000 individuals.
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
Abstract.
Author URL.
Tyrrell J, Wood AR, Ames RM, Yaghootkar H, Beaumont RN, Jones SE, Tuke MA, Ruth KS, Freathy RM, Davey Smith G, et al (2017). Gene-obesogenic environment interactions in the UK Biobank study.
Int J Epidemiol,
46(2), 559-575.
Abstract:
Gene-obesogenic environment interactions in the UK Biobank study.
BACKGROUND: Previous studies have suggested that modern obesogenic environments accentuate the genetic risk of obesity. However, these studies have proven controversial as to which, if any, measures of the environment accentuate genetic susceptibility to high body mass index (BMI). METHODS: We used up to 120 000 adults from the UK Biobank study to test the hypothesis that high-risk obesogenic environments and behaviours accentuate genetic susceptibility to obesity. We used BMI as the outcome and a 69-variant genetic risk score (GRS) for obesity and 12 measures of the obesogenic environment as exposures. These measures included Townsend deprivation index (TDI) as a measure of socio-economic position, TV watching, a 'Westernized' diet and physical activity. We performed several negative control tests, including randomly selecting groups of different average BMIs, using a simulated environment and including sun-protection use as an environment. RESULTS: We found gene-environment interactions with TDI (Pinteraction = 3 × 10 -10 ), self-reported TV watching (Pinteraction = 7 × 10 -5 ) and self-reported physical activity (Pinteraction = 5 × 10 -6 ). Within the group of 50% living in the most relatively deprived situations, carrying 10 additional BMI-raising alleles was associated with approximately 3.8 kg extra weight in someone 1.73 m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMI-raising alleles was associated with approximately 2.9 kg extra weight. The interactions were weaker, but present, with the negative controls, including sun-protection use, indicating that residual confounding is likely. CONCLUSIONS: Our findings suggest that the obesogenic environment accentuates the risk of obesity in genetically susceptible adults. of the factors we tested, relative social deprivation best captures the aspects of the obesogenic environment responsible.
Abstract.
Author URL.
Lotta LA, Gulati P, Day FR, Payne F, Ongen H, van de Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, et al (2017). Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
Nat Genet,
49(1), 17-26.
Abstract:
Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
Abstract.
Author URL.
Yaghootkar H, Bancks MP, Jones SE, McDaid A, Beaumont R, Donnelly L, Wood AR, Campbell A, Tyrrell J, Hocking LJ, et al (2017). Quantifying the extent to which index event biases influence large genetic association studies.
Hum Mol Genet,
26(5), 1018-1030.
Abstract:
Quantifying the extent to which index event biases influence large genetic association studies.
As genetic association studies increase in size to 100 000s of individuals, subtle biases may influence conclusions. One possible bias is 'index event bias' (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analyzing data from 113 203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (body mass index (BMI) decreasing) and one (near MTNR1B) underestimated (BMI increasing) associations among 11 type 2 diabetes risk alleles (at P < 0.05). IEB became even stronger when we tested a type 2 diabetes genetic risk score composed of these 11 variants (-0.010 standard deviations BMI per allele, P = 5 × 10- 4), which was confirmed in four additional independent studies. Similar results emerged when examining the effect of blood pressure increasing alleles on BMI in normotensive UK Biobank samples. Furthermore, we demonstrated that, under realistic scenarios, common disease alleles would become associated at P < 5 × 10- 8 with disease-related traits through IEB alone, if disease prevalence in the sample differs appreciably from the background population prevalence. For example, some hypertension and type 2 diabetes alleles will be associated with BMI in sample sizes of >500 000 if the prevalence of those diseases differs by >10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.
Abstract.
Author URL.
Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C, Highland HM, et al (2017). Rare and low-frequency coding variants alter human adult height.
Nature,
542(7640), 186-190.
Abstract:
Rare and low-frequency coding variants alter human adult height.
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
Abstract.
Author URL.
Pilling LC, Atkins JL, Duff MO, Beaumont RN, Jones SE, Tyrrell J, Kuo C-L, Ruth KS, Tuke MA, Yaghootkar H, et al (2017). Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.
PLoS One,
12(9).
Abstract:
Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.
INTRODUCTION: Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. RESULTS: a large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%,
Abstract.
Author URL.
Flannick J, Fuchsberger C, Mahajan A, Teslovich TM, Agarwala V, Gaulton KJ, Caulkins L, Koesterer R, Ma C, Moutsianas L, et al (2017). Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.
Sci Data,
4Abstract:
Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.
To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
Abstract.
Author URL.
Scott RA, Freitag DF, Li L, Chu AY, Surendran P, Young R, Grarup N, Stancáková A, Chen Y, Varga TV, et al (2016). A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
Sci Transl Med,
8(341).
Abstract:
A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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Author URL.
McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, Kang HM, Fuchsberger C, Danecek P, Sharp K, et al (2016). A reference panel of 64,976 haplotypes for genotype imputation.
Nat Genet,
48(10), 1279-1283.
Abstract:
A reference panel of 64,976 haplotypes for genotype imputation.
We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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Author URL.
Frayling TM, Tyrrell J (2016). Authors' reply to Toth.
BMJ,
353 Author URL.
Pitt A, Knight BA, Hudson M, Beall L, Hattersley AT, Jones AG, Frayling TM (2016). Evaluating the Exeter Glucose Potentiated Arginine Insulin Secretion (E-GPAIS) test for recruit by genotype studies.
DIABETIC MEDICINE,
33, 29-29.
Author URL.
Lee BP, Lloyd-Laney HO, Locke JM, McCulloch LJ, Knight B, Yaghootkar H, Cory G, Kos K, Frayling TM, Harries LW, et al (2016). Functional characterisation of ADIPOQ variants using individuals recruited by genotype.
Mol Cell Endocrinol,
428, 49-57.
Abstract:
Functional characterisation of ADIPOQ variants using individuals recruited by genotype.
Four non-coding GWAS variants in or near the ADIPOQ gene (rs17300539, rs17366653, rs3821799 and rs56354395) together explain 4% of the variation in circulating adiponectin. The functional basis for this is unknown. We tested the effect of these variants on ADIPOQ transcription, splicing and stability respectively in adipose tissue samples from participants recruited by rs17366653 genotype. Transcripts carrying rs17300539 demonstrated a 17% increase in expression (p = 0.001). Variant rs17366653 was associated with disruption of ADIPOQ splicing leading to a 7 fold increase in levels of a non-functional transcript (p = 0.002). Transcripts carrying rs56354395 demonstrated a 59% decrease in expression (p =
Abstract.
Author URL.
Tyrrell J, Richmond RC, Palmer TM, Feenstra B, Rangarajan J, Metrustry S, Cavadino A, Paternoster L, Armstrong LL, De Silva NMG, et al (2016). Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. JAMA, 315(11), 1129-1129.
Yaghootkar H, Lotta LA, Tyrrell J, Smit RAJ, Jones SE, Donnelly L, Beaumont R, Campbell A, Tuke MA, Hayward C, et al (2016). Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.
Diabetes,
65(8), 2448-2460.
Abstract:
Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.
Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These "favorable adiposity" alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m(2) [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic -0.859 mmHg [-1.099, -0.618]; P = 3E-12 and diastolic -0.394 mmHg [-0.534, -0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (-0.004 cm [95% CI -0.005, -0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.
Abstract.
Author URL.
Ruth KS, Beaumont RN, Tyrrell J, Jones SE, Tuke MA, Yaghootkar H, Wood AR, Freathy RM, Weedon MN, Frayling TM, et al (2016). Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.
Hum Reprod,
31(2), 473-481.
Abstract:
Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.
STUDY QUESTION: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? SUMMARY ANSWER: the T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. WHAT IS KNOWN ALREADY: the FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. MAIN RESULTS AND THE ROLE OF CHANCE: the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 × 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 × 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 × 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 × 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 × 10(-9)). LIMITATIONS, REASONS FOR CAUTION: the data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. WIDER IMPLICATIONS OF THE FINDINGS: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.
Abstract.
Author URL.
Jones SE, Tyrrell J, Wood AR, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Hu Y, Teder-Laving M, Hayward C, et al (2016). Genome-wide association analyses in 128,266 individuals identifies new morningness and sleep duration loci. PLoS Genetics
Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, van Zuydam NR, Gaulton KJ, Grarup N, et al (2016). Genome-wide associations for birth weight and correlations with adult disease.
Nature,
538(7624), 248-252.
Abstract:
Genome-wide associations for birth weight and correlations with adult disease.
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P
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Author URL.
Kilpeläinen TO, Carli JFM, Skowronski AA, Sun Q, Kriebel J, Feitosa MF, Hedman ÅK, Drong AW, Hayes JE, Zhao J, et al (2016). Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.
Nat Commun,
7Abstract:
Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P
Abstract.
Author URL.
Frayling TM, Tyrrell J (2016). HEIGHT, BODY MASS INDEX, AND SOCIOECONOMIC STATUS Conclusions of study on height, body mass index, and socioeconomic status have an uncertain basis Reply.
BMJ-BRITISH MEDICAL JOURNAL,
353 Author URL.
Frayling TM, Tyrrell J, Jones SE, Beaumont R, Astley CM, Lovell R, Yaghootkar H, Tuke M, Ruth KS, Freathy RM, et al (2016). Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank. British Medical Journal
Pilling LC, Atkins JL, Bowman K, Jones SE, Tyrrell J, Beaumont RN, Ruth KS, Tuke MA, Yaghootkar H, Wood AR, et al (2016). Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Aging (Albany NY),
8(3), 547-560.
Abstract:
Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.
Abstract.
Author URL.
Knowles JW, Xie W, Zhang Z, Chennamsetty I, Assimes TL, Paananen J, Hansson O, Pankow J, Goodarzi MO, Carcamo-Orive I, et al (2016). Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.
J Clin Invest,
126(1).
Author URL.
Scelo G, Hofmann JN, Banks RE, Bigot P, Bhatt RS, Cancel-Tassin G, Chew SK, Creighton CJ, Cussenot O, Davis IJ, et al (2016). International cancer seminars: a focus on kidney cancer.
Ann Oncol,
27(8), 1382-1385.
Abstract:
International cancer seminars: a focus on kidney cancer.
Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.
Abstract.
Author URL.
Lessard S, Manning AK, Low-Kam C, Auer PL, Giri A, Graff M, Schurmann C, Yaghootkar H, Luan J, Esko T, et al (2016). Testing the role of predicted gene knockouts in human anthropometric trait variation.
Hum Mol Genet,
25(10), 2082-2092.
Abstract:
Testing the role of predicted gene knockouts in human anthropometric trait variation.
Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7×), and >100 000 participants from the Genetic Investigation of ANthropometric Traits (GIANT) Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population.
Abstract.
Author URL.
Wood AR, Tyrrell J, Beaumont R, Jones SE, Tuke MA, Ruth KS, GIANT consortium, Yaghootkar H, Freathy RM, Murray A, et al (2016). Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively.
Diabetologia,
59(6), 1214-1221.
Abstract:
Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively.
AIMS/HYPOTHESIS: Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases. METHODS: We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity. RESULTS: Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p DOMDEV = 3 × 10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p DOMDEV = 0.003; meta-analysis p DOMDEV = 1 × 10(-7)). For type 2 diabetes, we detected a recessive effect (p DOMDEV = 5 × 10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance. CONCLUSIONS/INTERPRETATION: Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci. ACCESS TO RESEARCH MATERIALS: Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.
Abstract.
Author URL.
van der Valk RJP, Kreiner-Møller E, Kooijman MN, Guxens M, Stergiakouli E, Sääf A, Bradfield JP, Geller F, Hayes MG, Cousminer DL, et al (2015). A novel common variant in DCST2 is associated with length in early life and height in adulthood.
Hum Mol Genet,
24(4), 1155-1168.
Abstract:
A novel common variant in DCST2 is associated with length in early life and height in adulthood.
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
Abstract.
Author URL.
Sapin E, Keedwell E, Frayling T (2015). An Ant Colony Optimization and Tabu List Approach to the Detection of Gene-Gene Interactions in Genome-Wide Association Studies [Research Frontier].
IEEE Computational Intelligence Magazine,
10(4), 54-65.
Abstract:
An Ant Colony Optimization and Tabu List Approach to the Detection of Gene-Gene Interactions in Genome-Wide Association Studies [Research Frontier]
In this paper, a novel ant colony optimization and tabu list approach for the discovery of gene-gene interactions in genome-wide association study data is proposed. The method is tested on a number of diseases drawn from the large established database, the Wellcome Trust Case Control Consortium which contains hundreds of thousands of small DNA changes known as single nucleotide polymorphisms. To analyze full scale genome-wide association study data, the standard ant colony optimization algorithm has been adapted, with tournament path selection, a subset based approach, and tabu list included in the algorithm. These modifications, in addition to the use of a statistical test of significance of single nucleotide polymorphism interactions as a fitness function, greatly increase execution speeds and permit the discovery of combinations of single nucleotide polymorphisms that can discriminate cases and controls. The methodology is applied to several large-scale genome-wide association study disease datasets namely, inflammatory bowel disease, rheumatoid arthritis, type I diabetes and type II diabetes patients to discover putative gene-gene interactions in reasonable time on modest hardware.
Abstract.
Sapin E, Frayling T, Keedwell EC (2015). Ant colony optimisation of decision tree and contingency table models for the discovery of gene–gene interactions. IET Systems Biology
Yaghootkar H, Stancáková A, Freathy RM, Vangipurapu J, Weedon MN, Xie W, Wood AR, Ferrannini E, Mari A, Ring SM, et al (2015). Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.
Diabetes,
64(6), 2279-2285.
Abstract:
Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.
A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.
Abstract.
Author URL.
Pers TH, Karjalainen JM, Chan Y, Westra H-J, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, et al (2015). Biological interpretation of genome-wide association studies using predicted gene functions.
Nat Commun,
6Abstract:
Biological interpretation of genome-wide association studies using predicted gene functions.
The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.
Abstract.
Author URL.
Nead KT, Li A, Wehner MR, Neupane B, Gustafsson S, Butterworth A, Engert JC, Davis AD, Hegele RA, Miller R, et al (2015). Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.
Hum Mol Genet,
24(12), 3582-3594.
Abstract:
Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.
Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.
Abstract.
Author URL.
Moore AZ, Ding J, Tuke MA, Wood A, Melzer D, Bandinelli S, Frayling T, Ferrucci L (2015). DISTRIBUTION OF MITOCHONDRIAL DNA HETEROPLASMY IN PARTICIPANTS OF THE INCHIANTI STUDY.
GERONTOLOGIST,
55, 67-67.
Author URL.
Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C, Smith AV, Zhang W, et al (2015). Directional dominance on stature and cognition in diverse human populations.
Nature,
523(7561), 459-462.
Abstract:
Directional dominance on stature and cognition in diverse human populations.
Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
Abstract.
Author URL.
Gaulton KJ, Ferreira T, Lee Y, Raimondo A, Mägi R, Reschen ME, Mahajan A, Locke A, Rayner NW, Robertson N, et al (2015). Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Nature Genetics,
47(12), 1415-1425.
Abstract:
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Abstract.
Gaulton KJ, Ferreira T, Lee Y, Raimondo A, Mägi R, Reschen ME, Mahajan A, Locke A, Rayner NW, Robertson N, et al (2015). Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Nat Genet,
47(12), 1415-1425.
Abstract:
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Abstract.
Author URL.
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, et al (2015). Genetic studies of body mass index yield new insights for obesity biology.
Nature,
518(7538), 197-206.
Abstract:
Genetic studies of body mass index yield new insights for obesity biology.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Abstract.
Author URL.
Mahajan A, Sim X, Ng HJ, Manning A, Rivas MA, Highland HM, Locke AE, Grarup N, Im HK, Cingolani P, et al (2015). Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
PLoS Genetics,
11(1).
Abstract:
Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus
Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P
Abstract.
Knowles JW, Xie W, Zhang Z, Chennemsetty I, Assimes TL, Paananen J, Hansson O, Pankow J, Goodarzi MO, Carcamo-Orive I, et al (2015). Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.
Journal of Clinical Investigation,
125(4), 1739-1751.
Abstract:
Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol- stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
Abstract.
Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, Dauriz M, Hivert M-F, Raghavan S, Lipovich L, et al (2015). Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
Nat Commun,
6Abstract:
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Abstract.
Author URL.
Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, Strawbridge RJ, Pers TH, Fischer K, Justice AE, et al (2015). New genetic loci link adipose and insulin biology to body fat distribution.
Nature,
518(7538), 187-196.
Abstract:
New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P
Abstract.
Author URL.
Robinson MR, Hemani G, Medina-Gomez C, Mezzavilla M, Esko T, Shakhbazov K, Powell JE, Vinkhuyzen A, Berndt SI, Gustafsson S, et al (2015). Population genetic differentiation of height and body mass index across Europe.
Nature GeneticsAbstract:
Population genetic differentiation of height and body mass index across Europe
Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10-8; BMI, P < 5.95 × 10-4), and we find an among-population genetic correlation for tall and slender individuals (r = −0.80, 95% CI = −0.95, −0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).
Abstract.
Robinson MR, Hemani G, Medina-Gomez C, Mezzavilla M, Esko T, Shakhbazov K, Powell JE, Vinkhuyzen A, Berndt SI, Gustafsson S, et al (2015). Population genetic differentiation of height and body mass index across Europe.
Nature Genetics,
47(11), 1357-1361.
Abstract:
Population genetic differentiation of height and body mass index across Europe
Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10 -8; BMI, P < 5.95 × 10 -4), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).
Abstract.
Frayling TM (2015). Statins and type 2 diabetes: genetic studies on target.
Lancet,
385(9965), 310-312.
Author URL.
Usher CL, Handsaker RE, Esko T, Tuke MA, Weedon MN, Hastie AR, Cao H, Moon JE, Kashin S, Fuchsberger C, et al (2015). Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity.
Nature Genetics,
47(8), 921-925.
Abstract:
Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity
Hundreds of genes reside in structurally complex, poorly understood regions of the human genome. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity, although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis, droplet digital PCR and genome mapping, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling â 1/43,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI, yet found no association.
Abstract.
Usher CL, Handsaker RE, Esko T, Tuke MA, Weedon MN, Hastie AR, Cao H, Moon JE, Kashin S, Fuchsberger C, et al (2015). Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity.
Nat Genet,
47(8), 921-925.
Abstract:
Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity.
Hundreds of genes reside in structurally complex, poorly understood regions of the human genome. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity, although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis, droplet digital PCR and genome mapping, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling ∼3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI, yet found no association.
Abstract.
Author URL.
Boquete Vilariño L, Frayling TM (2015). The Hunt for Low-Frequency Alleles Predisposing to Type 2 Diabetes and Related Cardiovascular Risk Factors.
Current Cardiovascular Risk Reports,
9(11).
Abstract:
The Hunt for Low-Frequency Alleles Predisposing to Type 2 Diabetes and Related Cardiovascular Risk Factors
Research into the genetic basis of cardiovascular-related diseases is moving at an extremely fast pace. Developments in technology such as whole-genome sequencing and massive resources of DNA collected from hundreds of thousands of people mean scientists have an unprecedented ability to discover the genetic variation that predisposes to disease. Before 2007, very little was known about the variation in the human DNA sequence and its influence on common diseases. We now know of hundreds of common variants that influence LDL cholesterol levels, type 2 diabetes, hypertension and heart disease to name a few. Attention has now turned to the discovery of the genetic variants that occur in between 1 in 20 and 1 in 1000 individuals. These variants are unlikely to cause disease in the same way that mutations in some genes cause a monogenic disorder with a particular pattern of inheritance. But variants in this frequency range will shed light on biological mechanisms of disease. In this review, we focus on these variants and discuss how a range of study designs have identified low-frequency genetic variants with stronger predisposing effects on type 2 diabetes and related traits than common genetic variants.
Abstract.
Fall T, Xie W, Poon W, Yaghootkar H, Mägi R, GENESIS Consortium, Knowles JW, Lyssenko V, Weedon M, Frayling TM, et al (2015). Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes.
Diabetes,
64(7), 2676-2684.
Abstract:
Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes.
The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication and Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = -0.21, P = 5 × 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.
Abstract.
Author URL.
Wood AR, Tuke MA, Nalls M, Hernandez D, Gibbs JR, Lin H, Xu CS, Li Q, Shen J, Jun G, et al (2015). Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.
Hum Mol Genet,
24(5), 1504-1512.
Abstract:
Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.
Initial results from sequencing studies suggest that there are relatively few low-frequency (
Abstract.
Author URL.
Prokopenko I, Poon W, Mägi R, Prasad B R, Salehi SA, Almgren P, Osmark P, Bouatia-Naji N, Wierup N, Fall T, et al (2014). A central role for GRB10 in regulation of islet function in man.
PLoS Genet,
10(4).
Abstract:
A central role for GRB10 in regulation of islet function in man.
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
Abstract.
Author URL.
Ghanbari M, de Vries PS, de Looper H, Peters MJ, Schurmann C, Yaghootkar H, Dörr M, Frayling TM, Uitterlinden AG, Hofman A, et al (2014). A genetic variant in the seed region of miR-4513 shows pleiotropic effects on lipid and glucose homeostasis, blood pressure, and coronary artery disease.
Hum Mutat,
35(12), 1524-1531.
Abstract:
A genetic variant in the seed region of miR-4513 shows pleiotropic effects on lipid and glucose homeostasis, blood pressure, and coronary artery disease.
MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein-cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3, and GOSR2) through which these effects might be taking place. Using luciferase reporter assays, we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA-mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases.
Abstract.
Author URL.
Wood AR, Tuke MA, Nalls MA, Hernandez DG, Bandinelli S, Singleton AB, Melzer D, Ferrucci L, Frayling TM, Weedon MN, et al (2014). Another explanation for apparent epistasis.
Nature,
514(7520), E3-E5.
Author URL.
Vimaleswaran KS, Cavadino A, Berry DJ, Power C, Hyppönen E, Jorde R, Grimnes G, Dieff enbach AK, Schöttker B, Saum KU, et al (2014). Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
The Lancet Diabetes and Endocrinology,
2(9), 719-729.
Abstract:
Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study
Background: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods: in this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings: in phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). Interpretation: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. Funding: British Heart Foundation, UK Medical Research Council, and Academy of Finland.
Abstract.
Vimaleswaran KS, Cavadino A, Berry DJ, LifeLines Cohort Study investigators, Jorde R, Dieffenbach AK, Lu C, Alves AC, Heerspink HJL, Tikkanen E, et al (2014). Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
Lancet Diabetes Endocrinol,
2(9), 719-729.
Abstract:
Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: in this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: in phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. FUNDING: British Heart Foundation, UK Medical Research Council, and Academy of Finland.
Abstract.
Author URL.
Scott RA, Fall T, Pasko D, Barker A, Sharp SJ, Arriola L, Balkau B, Barricarte A, Barroso I, Boeing H, et al (2014). Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.
Diabetes,
63(12), 4378-4387.
Abstract:
Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity.
We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
Abstract.
Author URL.
Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, et al (2014). Defining the role of common variation in the genomic and biological architecture of adult human height.
Nature Genetics,
46(11), 1173-1186.
Abstract:
Defining the role of common variation in the genomic and biological architecture of adult human height
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Abstract.
Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, et al (2014). Defining the role of common variation in the genomic and biological architecture of adult human height.
Nat Genet,
46(11), 1173-1186.
Abstract:
Defining the role of common variation in the genomic and biological architecture of adult human height.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Abstract.
Author URL.
Elliott HR, Tillin T, McArdle WL, Ho K, Duggirala A, Frayling TM, Smith GD, Hughes AD, Chaturvedi N, Relton CL, et al (2014). Differences in smoking associated DNA methylation patterns in South Asians and Europeans.
CLINICAL EPIGENETICS,
6 Author URL.
Hassanali N, De Silva NMG, Robertson N, Rayner NW, Barrett A, Bennett AJ, Groves CJ, Matthews DR, Katulanda P, Frayling TM, et al (2014). Evaluation of common type 2 diabetes risk variants in a South Asian population of Sri Lankan descent.
PLoS One,
9(6).
Abstract:
Evaluation of common type 2 diabetes risk variants in a South Asian population of Sri Lankan descent.
INTRODUCTION: Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka. METHODOLOGY: Lead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population. RESULTS: of the 36 SNPs passing quality control, sixteen showed nominal (p
Abstract.
Author URL.
Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Walker M, et al (2014). Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.
Diabetes,
63(12), 4369-4377.
Abstract:
Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.
The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
Abstract.
Author URL.
Frayling TM (2014). Genome-wide association studies: the good, the bad and the ugly.
Clin Med (Lond),
14(4), 428-431.
Author URL.
Mahajan A, Go MJ, Zhang W, Below JE, Gaulton KJ, Ferreira T, Horikoshi M, Johnson AD, Ng MCY, Prokopenko I, et al (2014). Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
NATURE GENETICS,
46(3), 234-+.
Author URL.
Medici M, Porcu E, Pistis G, Teumer A, Brown SJ, Jensen RA, Rawal R, Roef GL, Plantinga TS, Vermeulen SH, et al (2014). Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
PLoS Genet,
10(2).
Abstract:
Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P
Abstract.
Author URL.
Hoggart CJ, Venturini G, Mangino M, Gomez F, Ascari G, Zhao JH, Teumer A, Winkler TW, Tšernikova N, Luan J, et al (2014). Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
PLoS Genet,
10(7).
Abstract:
Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P
Abstract.
Author URL.
Frayling TM, Hattersley AT (2014). Physiology helps GWAS take a step closer to mechanism.
Diabetes,
63(6), 1836-1837.
Author URL.
Majithia AR, Flannick J, Shahinian P, Guo M, Bray MA, Fontanillas P, Gabriel SB, Manning AK, Hartl C, Agarwala V, et al (2014). Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes.
Proceedings of the National Academy of Sciences of the United States of America,
111(36), 13127-13132.
Abstract:
Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes
Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and a canonical target of antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy and insulin resistance; in the general population, the common P12A variant is associated with a decreased risk of type 2 diabetes (T2D). Whether and how rare variants in PPARG and defects in adipocyte differentiation influence risk of T2D in the general population remains undetermined. By sequencing PPARG in 19,752 T2D cases and controls drawn from multiple studies and ethnic groups, we identified 49 previously unidentified, nonsynonymous PPARG variants (MAF < 0.5%). Considered in aggregate (with or without computational prediction of functional consequence), these rare variants showed no association with T2D (OR = 1.35; P = 0.17). The function of the 49 variants was experimentally tested in a novel high-throughput human adipocyte differentiation assay, and nine were found to have reduced activity in the assay. Carrying any of these nine LOF variants was associated with a substantial increase in risk of T2D (OR = 7.22; P = 0.005). The combination of large-scale DNA sequencing and functional testing in the laboratory reveals that approximately 1 in 1,000 individuals carries a variant in PPARG that reduces function in a human adipocyte differentiation assay and is associated with a substantial risk of T2D.
Abstract.
Taylor AE, Morris RW, Fluharty ME, Bjorngaard JH, Åsvold BO, Gabrielsen ME, Campbell A, Marioni R, Kumari M, Hällfors J, et al (2014). Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.
PLoS Genet,
10(12).
Abstract:
Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.
We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.
Abstract.
Author URL.
Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, et al (2013). A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function.
PLoS Genetics,
9(2).
Abstract:
A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Abstract.
Thorgeirsson TE, Gudbjartsson DF, Sulem P, Besenbacher S, Styrkarsdottir U, Thorleifsson G, Walters GB, Furberg H, Sullivan PF, Marchini J, et al (2013). A common biological basis of obesity and nicotine addiction.
Translational Psychiatry,
3, 1-7.
Abstract:
A common biological basis of obesity and nicotine addiction
Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10-7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10-5) and CPD (P=9.3 × 10-5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity. © 2013 Macmillan Publishers Limited.
Abstract.
Menni C, Fauman E, Erte I, Perry JRB, Kastenmüller G, Shin SY, Petersen AK, Hyde C, Psatha M, Ward KJ, et al (2013). Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.
Diabetes,
62(12), 4270-4276.
Abstract:
Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach
Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large populationbased cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39-1.95], P = 8.46 3 1029) and was moderately heritable (h2 = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34-2.11], P = 6.52 3 1026) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27-2.75], P = 1 3 1023). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms. © 2013 by the American Diabetes Association.
Abstract.
Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, et al (2013). Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts.
PLoS Medicine,
10(2).
Abstract:
Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10-27). The BMI allele score was associated both with BMI (p = 6.30×10-62) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10-57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). Conclusions: on the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors' Summary. © 2013 Vimaleswaran et al.
Abstract.
Albrechtsen A, Grarup N, Li Y, Sparso T, Tian G, Cao H, Jiang T, Kim SY, Korneliussen T, Li Q, et al (2013). Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.
DIABETOLOGIA,
56(2), 298-310.
Author URL.
Xie W, Wood AR, Lyssenko V, Weedon MN, Knowles JW, Alkayyali S, Assimes TL, Quertermous T, Abbasi F, Paananen J, et al (2013). Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
Diabetes,
62(6), 2141-2150.
Abstract:
Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
Abstract.
Author URL.
Crosslin DR, McDavid A, Weston N, Zheng X, Hart E, de Andrade M, Kullo IJ, McCarty CA, Doheny KF, Pugh E, et al (2013). Genetic variation associated with circulating monocyte count in the eMERGE Network.
Human Molecular Genetics,
22(10), 2119-2127.
Abstract:
Genetic variation associated with circulating monocyte count in the eMERGE Network
With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genomewide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value =2.7x10(-16), β=-0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value =1.88x10(-7), β=0.30) and a region of replication found in ribophorin I (RPN1) (P-value=2.63x10(-16), β=-0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value =2.29x10(-7), β=0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value =5.68x10(-17), β=-0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count. © the Author 2013. Published by Oxford University Press. All rights reserved.
Abstract.
Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau-Chonka DC, Day FR, et al (2013). Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Nature Genetics,
45(5), 501-512.
Abstract:
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.
Abstract.
Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau-Chonka DC, Day FR, et al (2013). Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature Genetics
Wood AR, Perry JRB, Tanaka T, Hernandez DG, Zheng H-F, Melzer D, Gibbs JR, Nalls MA, Weedon MN, Spector TD, et al (2013). Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation.
PLoS One,
8(5).
Abstract:
Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation.
Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF
Abstract.
Author URL.
Yaghootkar H, Lamina C, Scott RA, Dastani Z, Hivert M-F, Warren LL, Stancakova A, Buxbaum SG, Lyytikaeinen L-P, Henneman P, et al (2013). Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes.
DIABETES,
62(10), 3589-3598.
Author URL.
Yaghootkar H, Lamina C, Scott R, Dastani Z, Hivert MF, Lawlor D, Meigs J, Richards B, Frayling T (2013). Mendelian randomisation studies do not support a causal role for reduced circulating adiponectin levels in fasting based measures of insulin resistance and Type 2 diabetes.
DIABETIC MEDICINE,
30, 30-30.
Author URL.
Horikoshi M, Yaghootkar H, Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ, Bradfield JP, St Pourcain B, Evans DM, Charoen P, et al (2013). New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
Nature Genetics,
45(1), 76-82.
Abstract:
New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. © 2013 Nature America, Inc. All rights reserved.
Abstract.
Tyrrell JS, Yaghootkar H, Freathy RM, Hattersley AT, Frayling TM (2013). Parental diabetes and birthweight in 236 030 individuals in the UK biobank study.
Int J Epidemiol,
42(6), 1714-1723.
Abstract:
Parental diabetes and birthweight in 236 030 individuals in the UK biobank study.
BACKGROUND: the UK Biobank study provides a unique opportunity to study the causes and consequences of disease. We aimed to use the UK Biobank data to study the well-established, but poorly understood, association between low birthweight and type 2 diabetes. METHODS: We used logistic regression to calculate the odds ratio for participants' risk of type 2 diabetes given a one standard deviation increase in birthweight. To test for an association between parental diabetes and birthweight, we performed linear regression of self-reported parental diabetes status against birthweight. We performed path and mediation analyses to test the hypothesis that birthweight partly mediates the association between parental diabetes and participant type 2 diabetes status. RESULTS: of the UK Biobank participants, 277 261 reported their birthweight. of 257 715 individuals of White ethnicity and singleton pregnancies, 6576 had type 2 diabetes, 19 478 reported maternal diabetes (but not paternal), 20 057 reported paternal diabetes (but not maternal) and 2754 participants reported both parents as having diabetes. Lower birthweight was associated with type 2 diabetes in the UK Biobank participants. A one kilogram increase in birthweight was associated with a lower risk of type 2 diabetes (odds ratio: 0.74; 95% CI: 0.71, 0.76; P = 2 × 10(-57)). Paternal diabetes was associated with lower birthweight (45 g lower; 95% CI: 36, 54; P = 2 × 10(-23)) relative to individuals with no parental diabetes. Maternal diabetes was associated with higher birthweight (59 g increase; 95% CI: 50, 68; P = 3 × 10(-37)). Participants' lower birthweight was a mediator of the association between reported paternal diabetes and participants' type 2 diabetes status, explaining 1.1% of the association, and participants' higher birthweight was a mediator of the association between reported maternal diabetes and participants' type 2 diabetes status, explaining 1.2% of the association. CONCLUSIONS: Data from the UK Biobank provides the strongest evidence by far that paternal diabetes is associated with lower birthweight, whereas maternal diabetes is associated with increased birthweight. Our findings with paternal diabetes are consistent with a role for the same genetic factors influencing foetal growth and type 2 diabetes.
Abstract.
Author URL.
Pennell CE, Vadillo-Ortega F, Olson DM, Ha E-H, Williams S, Frayling TM, Dolan S, Katz M, Merialdi M, Menon R, et al (2013). Preterm Birth Genome Project (PGP) - validation of resources for preterm birth genome-wide studies.
JOURNAL OF PERINATAL MEDICINE,
41(1), 45-49.
Author URL.
Yaghootkar H, Frayling TM (2013). Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits.
Genome Biol,
14(3).
Abstract:
Recent progress in the use of genetics to understand links between type 2 diabetes and related metabolic traits.
Genome-wide association studies have identified genetic variants associated with increased risk of type 2 diabetes. The aim of this review is to highlight some of the insights into the mechanism underlying type 2 diabetes provided by genetic association studies.
Abstract.
Author URL.
Randall JC, Winkler TW, Kutalik Z, Berndt SI, Jackson AU, Monda KL, Kilpeläinen TO, Esko T, Mägi R, Li S, et al (2013). Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits.
PLoS Genetics,
9(6).
Abstract:
Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR
Abstract.
Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, et al (2013). Systematic identification of trans eQTLs as putative drivers of known disease associations.
Nature Genetics,
45(10), 1238-1243.
Abstract:
Systematic identification of trans eQTLs as putative drivers of known disease associations
Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3′ UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants. © 2013 Nature America, Inc. All rights reserved.
Abstract.
Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, et al (2013). Systematic identification of trans eQTLs as putative drivers of known disease associations. Nature Genetics
Morrison FS, Locke JM, Wood AR, Tuke M, Pasko D, Murray A, Frayling T, Harries LW (2013). The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.
BMC Genomics,
14Abstract:
The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.
BACKGROUND: Many genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes. RESULTS: We identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2. CONCLUSIONS: Our findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.
Abstract.
Author URL.
Yang J, Loos RJF, Powell JE, Medland SE, Speliotes EK, Chasman DI, Rose LM, Thorleifsson G, Steinthorsdottir V, Maegi R, et al (2012). <i>FTO</i> genotype is associated with phenotypic variability of body mass index.
NATURE,
490(7419), 267-+.
Author URL.
Manning AK, Hivert MF, Scott RA, Grimsby JL, Bouatia-Naji N, Chen H, Rybin D, Liu CT, Bielak LF, Prokopenko I, et al (2012). A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.
Nature Genetics,
44(6), 659-669.
Abstract:
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10 -8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. © 2012 Nature America, Inc. All rights reserved.
Abstract.
Coviello AD, Haring R, Wellons M, Vaidya D, Lehtimäki T, Keildson S, Lunetta KL, He C, Fornage M, Lagou V, et al (2012). A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation.
PLoS Genetics,
8(7).
Abstract:
A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10-106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10-11), GCKR (rs780093, 2p23.3, p = 2.2×10-16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10-09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10-35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10-08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10-12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10-14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10-14), LHCGR (rs10454142, 2p16.3, p = 1.3×10-07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10-08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10-06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10-08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Abstract.
Frayling TM (2012). Are the causes of obesity primarily environmental? No.
BMJ,
345 Author URL.
Wilding J, Frayling TM (2012). Are the causes of obesity primarily environmental? Yes/No. BMJ (Online), 345(7875).
Taal HR, St Pourcain B, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Moller E, Bradfield JP, Freathy RM, et al (2012). Common variants at 12q15 and 12q24 are associated with infant head circumference.
NATURE GENETICS,
44(5), 532-+.
Author URL.
Ikram MA, Fornage M, Smith AV, Seshadri S, Schmidt R, Debette S, Vrooman HA, Sigurdsson S, Ropele S, Taal HR, et al (2012). Common variants at 6q22 and 17q21 are associated with intracranial volume.
NATURE GENETICS,
44(5), 539-+.
Author URL.
Yang J, Ferreira T, Morris AP, Medland SE, Madden PAF, Heath AC, Martin NG, Montgomery GW, Weedon MN, Loos RJ, et al (2012). Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits.
Nature Genetics,
44(4), 369-375.
Abstract:
Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits
We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium. © 2012 Nature America, Inc. All rights reserved.
Abstract.
Warren LL, Li L, Nelson MR, Ehm MG, Shen J, Fraser DJ, Aponte JL, Nangle KL, Slater AJ, Woollard PM, et al (2012). Deep resequencing unveils genetic architecture of ADIPOQ and identifies a novel low-frequency variant strongly associated with adiponectin variation.
Diabetes,
61(5), 1297-1301.
Abstract:
Deep resequencing unveils genetic architecture of ADIPOQ and identifies a novel low-frequency variant strongly associated with adiponectin variation
Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g. odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted. © 2012 by the American Diabetes Association.
Abstract.
Franceschini N, Van Rooij FJA, Prins BP, Feitosa MF, Karakas M, Eckfeldt JH, Folsom AR, Kopp J, Vaez A, Andrews JS, et al (2012). Discovery and fine mapping of serum protein loci through transethnic meta-analysis.
American Journal of Human Genetics,
91(4), 744-753.
Abstract:
Discovery and fine mapping of serum protein loci through transethnic meta-analysis
Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10-8) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease. © 2012 the American Society of Human Genetics.
Abstract.
Albrechtsen A, Grarup N, Li Y, Sparsø T, Tian G, Cao H, Jiang T, Kim SY, Korneliussen T, Li Q, et al (2012). Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia, 1-13.
Tyrrell J, Huikari V, Christie JT, Cavadino A, Bakker R, Brion M-JA, Geller F, Paternoster L, Myhre R, Potter C, et al (2012). Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.
Hum Mol Genet,
21(24), 5344-5358.
Abstract:
Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.
Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
Abstract.
Author URL.
Boraska V, Day-Williams A, Franklin CS, Elliott KS, Panoutsopoulou K, Tachmazidou I, Albrecht E, Bandinelli S, Beilin LJ, Bochud M, et al (2012). Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.
PLoS ONE,
7(3).
Abstract:
Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts
Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p
Abstract.
Boraska V, Jerončić A, Colonna V, Southam L, Nyholt DR, William rayner N, Perry JRB, Toniolo D, Albrecht E, Ang W, et al (2012). Genome-wide meta-analysis of common variant differences between men and women.
Human Molecular Genetics,
21(21), 4805-4815.
Abstract:
Genome-wide meta-analysis of common variant differences between men and women
The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10-8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits. © the Author 2012. Published by Oxford University Press.
Abstract.
Cauchi S, Perry J, Almgren P, Scott R, Langenberg C, Wareham N, Groop L, Frayling T, Froguel P (2012). Identification of new genetic polymorphisms linked to type 2 diabetes risk in obese and non-obese Europeans.
DIABETES & METABOLISM,
38, A61-A62.
Author URL.
Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H, Mahajan A, et al (2012). Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Nature Genetics,
44(9), 981-990.
Abstract:
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Abstract.
Fall T, Xie W, Hao K, Arnlov J, Abbasi F, Schadt EE, Boran G, Hansen T, Greenawalt D, Nolan JJ, et al (2012). Mendelian Randomization Studies Do Not Support a Causal Effect of Plasma Lipids on Insulin Sensitivity.
CIRCULATION,
126(21).
Author URL.
Islam M, Jafar TH, Wood AR, De Silva NMG, Caulfield M, Chaturvedi N, Frayling TM (2012). Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis.
Diabetologia,
55(8), 2193-2204.
Abstract:
Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis
Aims/hypothesis: Multiple genetic variants are associated with type 2 diabetes-related traits in Europeans, but their role in South Asian populations needs further study. We hypothesised that genetic variants associated with diabetesrelated traits in Europeans would explain a similar proportion of phenotypic variance in a Pakistani population and could be used in Mendelian randomisation analyses. Methods: We used data from 2,131 individuals from the Control of Blood Pressure and Risk Attenuation Trial (COBRA) in Karachi, Pakistan. Individuals were aged 40 years or older. Results: Combining information from multiple genetic variants showed that fasting glucose, BMI, triacylglycerol, and systolic and diastolic blood pressure variants explained 2.9%, 0.7%, 5.5%, 1.2% and 1.8% of the variance in those traits respectively. Genetic risk scores of fasting glucose, triacylglycerol, BMI, systolic blood pressure and diastolic blood pressure variants were associated with these traits, with per allele SD effects of 0.057 (95% CI 0.041, 0.074), p=3.44×10-12, 0.130 (95% CI 0.105, 0.155), p=2.9×10 -21, 0.04 (95% CI 0.014, 0.072), p=0.004, 0.031 (95% CI 0.016, 0.047), p=7.9×10-5, 0.028 (95% CI 0.015, 0.042), p=5.5×10 -5, respectively. These effects are consistent with those observed in Europeans, except that the effect of triacylglycerol variants in South Asians was slightly lower. Mendelian randomisation provided evidence that genetically influenced, raised triacylglycerol levels do not causally affect type 2 diabetes risk to the extent predicted from observational data (p=0.0003 for difference between observed and instrumental variables correlations). Conclusions/ interpretation: Genetic variants identified in Europeans are associated with type 2 diabetes-related traits in Pakistanis, with comparable effect sizes. Larger studies are needed to perform adequately powered Mendelian randomisation and help dissect the relationships between type 2 diabetes-related traits in diverse South Asian subgroups. © Springer-Verlag 2012.
Abstract.
Horikoshi M, Yaghootkar H, Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ, Bradfield JP, St Pourcain B, Evans DM, Charoen P, et al (2012). New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nature Genetics
Dastani Z, Hivert MF, Timpson NJ, Yuan X, Lyytikäinen LP, Tanaka T, Morris AP, Isaacs A, Lohman K, Qi L, et al (2012). Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
PLoS Genetics,
8(3).
Abstract:
Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p
Abstract.
Palmer CNA, Maglio C, Pirazzi C, Burza MA, Adiels M, Burch L, Donnelly LA, Colhoun H, Doney AS, Dillon JF, et al (2012). Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant.
PLoS ONE,
7(6).
Abstract:
Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant
Background: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity. Methods and Findings: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI
Abstract.
Winney B, Boumertit A, Day T, Davison D, Echeta C, Evseeva I, Hutnik K, Leslie S, Nicodemus K, Royrvik EC, et al (2012). People of the British Isles: Preliminary analysis of genotypes and surnames in a UK-control population.
European Journal of Human Genetics,
20(2), 203-210.
Abstract:
People of the British Isles: Preliminary analysis of genotypes and surnames in a UK-control population
There is a great deal of interest in a fine-scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to have a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. In this study, we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK-control population that can be used as a resource by the research community, as well as providing a fine-scale genetic information on the British population. So far, some 4000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3 km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1057 samples demonstrates the value of these samples for investigating a fine-scale population structure within the UK, and shows how this can be enhanced by the use of surnames. © 2012 Macmillan Publishers Limited all rights reserved.
Abstract.
Perry JRB, Voight BF, Yengo L, Amin N, Dupuis J, Ganser M, Grallert H, Navarro P, Li M, Qi L, et al (2012). Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
PLoS Genet,
8(5).
Abstract:
Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI
Abstract.
Author URL.
Voight BF, Kang HM, Ding J, Palmer CD, Sidore C, Chines PS, Burtt NP, Fuchsberger C, Li Y, Erdmann J, et al (2012). The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits.
PLoS Genetics,
8(8).
Abstract:
The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits
Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits. © 2012 Voight et al.
Abstract.
Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JEL, Shah T, Sofat R, Guo Y, Chung C, Peasey A, Pfister R, et al (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
The Lancet,
379(9822), 1214-1224.
Abstract:
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
Background a high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular infl ammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. Methods Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely effi cacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic fi ndings with the eff ects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. Findings in 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fi brinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of eff ects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10-5). Interpretation on the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in popu lations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.
Abstract.
Taylor PN, Panicker V, Sayers A, Shields B, Iqbal A, Bremner AP, Beilby JP, Leedman PJ, Hattersley AT, Vaidya B, et al (2011). A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.
Eur J Endocrinol,
164(5), 773-780.
Abstract:
A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.
OBJECTIVE: Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T(4)). DESIGN: Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T(4)). METHODS: Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T(3)), and T(4) levels. RESULTS: Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64 × 10(-10) 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T(4) (P=0.023, -0.07 s.d./allele, 95% CI -0.137, -0.01), no association was seen with free T(3) (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T(4) in 1981 (-0.068 s.d./allele, 95% CI -0.167, 0.031) and 1994 (-0.07 s.d./allele, 95% CI -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T(4). CONCLUSION: Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T(4) levels that are consistent over time and lost in individuals on l-T(4). These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.
Abstract.
Author URL.
Jafar-Mohammadi B, Groves CJ, Gjesing AP, Herrera BM, Winckler W, Stringham HM, Morris AP, Lauritzen T, Doney ASF, Morris AD, et al (2011). A role for coding functional variants in <i>HNF4A</i> in type 2 diabetes susceptibility.
DIABETOLOGIA,
54(1), 111-119.
Author URL.
Bown MJ, Jones GT, Harrison SC, Wright BJ, Bumpstead S, Baas AF, Gretarsdottir S, Badger SA, Bradley DT, Burnand K, et al (2011). Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.
American Journal of Human Genetics,
89(5), 619-627.
Abstract:
Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1
Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10 -5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. © 2011 the American Society of Human Genetics.
Abstract.
Paternoster L, Howe LD, Tilling K, Weedon MN, Freathy RM, Frayling TM, Kemp JP, Smith GD, Timpson NJ, Ring SM, et al (2011). Adult height variants affect birth length and growth rate in children.
Hum Mol Genet,
20(20), 4069-4075.
Abstract:
Adult height variants affect birth length and growth rate in children.
Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ∼10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth. A total of 7768 participants in the Avon Longitudinal Study of Parents and Children had data available. Individual growth trajectories from 0 to 10 years were estimated using mixed-effects linear spline models and differences in trajectories by individual SNPs and allelic score were determined. The allelic score was associated with birth length (0.026 cm increase per 'tall' allele, SE = 0.003, P = 1 × 10(-15), equivalent to 0.017 SD). There was little evidence of association between the allelic score and early infancy growth (0-3 months), but there was evidence of association between the allelic score and later growth. This association became stronger with each consecutive growth period, per 'tall' allele per month effects were 0.015 SD (3 months-1 year, SE = 0.004), 0.023 SD (1-3 years, SE = 0.003) and 0.028 SD (3-10 years, SE = 0.003). By age 10, the mean height difference between individuals with ≤170 versus ≥191 'tall' alleles (the top and bottom 10%) was 4.7 cm (0.8 SD), explaining ∼5% of the variance. There was evidence of associations with specific growth periods for some SNPs (rs3791675, EFEMP1 and rs6569648, L3MBTL3) and supportive evidence for previously reported age-dependent effects of HHIP and SOCS2 SNPs. SNPs associated with adult height influence birth length and have an increasing effect on growth from late infancy through to late childhood. By age 10, they explain half the height variance (∼5%) of that explained in adults (∼10%).
Abstract.
Author URL.
Wood AR, Hernandez DG, Nalls MA, Yaghootkar H, Gibbs JR, Harries LW, Chong S, Moore M, Weedon MN, Guralnik JM, et al (2011). Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association.
Hum Mol Genet,
20(20), 4082-4092.
Abstract:
Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association.
The identification of multiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism (SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P< 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs of SNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data from the 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work.
Abstract.
Author URL.
Rees SD, Islam M, Hydrie MZI, Chaudhary B, Bellary S, Hashmi S, O'Hare JP, Kumar S, Sanghera DK, Chaturvedi N, et al (2011). An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference.
Diabet Med,
28(6), 673-680.
Abstract:
An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference.
AIMS: a common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. METHODS: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. RESULTS: in the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ]. CONCLUSIONS: the strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.
Abstract.
Author URL.
Christmas J, Keedwell E, Frayling T, Perry J (2011). Ant Colony Optimisation to identify Genetic Disease Association for Type 2 Diabetes. Information Sciences, 181(9), 1609-1622.
Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjærg-Hansen A, Smith GD (2011). C-reactive protein levels and body mass index: Elucidating direction of causation through reciprocal Mendelian randomization.
International Journal of Obesity,
35(2), 300-308.
Abstract:
C-reactive protein levels and body mass index: Elucidating direction of causation through reciprocal Mendelian randomization
Context:The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.Objective:Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.Participants and methods:The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them.Results:Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in logCRP of 1.03 kg m-2 (95% confidence interval (95% CI): 1.00, 1.07), P0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in logCRP of 0.24 kg m-2 (95% CI: 0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006).Conclusions:Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components. © 2011 Macmillan Publishers Limited. All rights reserved.
Abstract.
Chan Y, Holmen OL, Dauber A, Vatten L, Havulinna AS, Skorpen F, Kvaløy K, Silander K, Nguyen TT, Willer C, et al (2011). Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals.
PLoS Genetics,
7(12).
Abstract:
Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals
Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ~1.5%), drawn from ~78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p
Abstract.
Zhai G, Teumer A, Stolk L, Perry JRB, Vandenput L, Coviello AD, Koster A, Bandinelli S, Bell JT, Bhasin S, et al (2011). EIGHT COMMON GENETIC VARIANTS ASSOCIATED WITH SERUM DHEAS LEVELS SUGGESTS a KEY ROLE IN AGEING MECHANISMS.
CLINICAL CHEMISTRY AND LABORATORY MEDICINE,
49, S425-S425.
Author URL.
Zhai G, Teumer A, Stolk L, Perry JRB, Vandenput L, Coviello AD, Koster A, Bell JT, Bhasin S, Eriksson J, et al (2011). Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms.
PLoS Genetics,
7(4).
Abstract:
Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Abstract.
Pennell CE, Warrington NM, Mook-Kanamori D, Lye SJ, Newnham JP, Palmer LJ, Jaddoe VWV, Freathy RM, Jacobssen B, Holloway J, et al (2011). Genetic Basis for Gestation Length.
REPRODUCTIVE SCIENCES,
18(3), 310A-310A.
Author URL.
Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, et al (2011). Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
Nature,
478(7367), 103-109.
Abstract:
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3 GUCY1B3, NPR3 C5orf23, ADM, FURIN FES, GOSR2, GNAS EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. © 2011 Macmillan Publishers Limited. All rights reserved.
Abstract.
Freathy RM, Kazeem GR, Morris RW, Johnson PCD, Paternoster L, Ebrahim S, Hattersley AT, Hill A, Hingorani AD, Holst C, et al (2011). Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.
Int J Epidemiol,
40(6), 1617-1628.
Abstract:
Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.
BACKGROUND: Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers. METHODS: We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24,198) and then tested for a genotype × smoking status interaction. RESULTS: There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m(2) [95% confidence interval (95% CI): -0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m(2) (95% CI: 0.13-0.31) lower BMI (P = 8 × 10(-6)). The effect size was larger in current [0.33 kg/m(2) lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 × 10(-5)], than in former smokers [0.16 kg/m(2) (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001). CONCLUSIONS: Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BMI.
Abstract.
Author URL.
Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS, et al (2011). Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.
Diabetes,
60(10), 2624-2634.
Abstract:
Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes
OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
Abstract.
Bell JT, Timpson NJ, Rayner NW, Zeggini E, Frayling TM, Hattersley AT, Morris AP, McCarthy MI (2011). Genome-wide association scan allowing for epistasis in type 2 diabetes.
Ann Hum Genet,
75(1), 10-19.
Abstract:
Genome-wide association scan allowing for epistasis in type 2 diabetes.
In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two-dimensional genome-wide association (GWA) scan using joint two-locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two-locus association at 79 SNP-pairs at a Bonferroni-corrected P-value = 0.05 (uncorrected P-value = 2.14 × 10⁻¹¹). The 79 pair-wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single-locus association signals (P-value = 5 × 10⁻⁴). Analyses conditional on the single-locus effects at TCF7L2 established that the joint two-locus results could be attributed to single-locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP-pairs with case-control and case-only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single-locus association can underlie and obscure multilocus findings.
Abstract.
Author URL.
Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, et al (2011). Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genetics, 43(11), 1131-1138.
Kooner JS, Saleheen D, Sim X, Sehmi J, Zhang W, Frossard P, Been LF, Chia KS, Dimas AS, Hassanali N, et al (2011). Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
Nature Genetics,
43(10), 984-989.
Abstract:
Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci
We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10 -4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10 -8 to P = 1.9 × 10 -11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10 -4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D. © 2011 Nature America, Inc. All rights reserved.
Abstract.
Yang J, Weedon MN, Purcell S, Lettre G, Estrada K, Willer CJ, Smith AV, Ingelsson E, O'Connell JR, Mangino M, et al (2011). Genomic inflation factors under polygenic inheritance.
European Journal of Human Genetics,
19(7), 807-812.
Abstract:
Genomic inflation factors under polygenic inheritance
Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and genomic control can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ∼4000 and ∼133 000 individuals. © 2011 Macmillan Publishers Limited all rights reserved.
Abstract.
Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM, Yaghootkar H, Dutta A, Murray A, Frayling TM, et al (2011). Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing.
Aging Cell,
10(5), 868-878.
Abstract:
Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing.
Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n= 58), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P
Abstract.
Author URL.
Yaghootkar H, Hernandez D, Nalls M, Wood A, Gibbs R, Harries L, Chong S, Moore M, Guralnik J, Bandinell S, et al (2011). Identifying likely causal connections between gene expression levels using a Mendelian randomization approach.
CLINICAL BIOCHEMISTRY,
44(13), S294-S294.
Author URL.
De Silva NMG, Freathy RM, Palmer TM, Donnelly LA, Luan J, Gaunt T, Langenberg C, Weedon MN, Shields B, Knight BA, et al (2011). Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.
Diabetes,
60(3), 1008-1018.
Abstract:
Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.
OBJECTIVE: the causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS: We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS: Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS: Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
Abstract.
Author URL.
Nalls MA, Couper DJ, Tanaka T, van Rooij FJA, Chen MH, Smith AV, Toniolo D, Zakai NA, Yang Q, Greinacher A, et al (2011). Multiple loci are associated with white blood cell phenotypes.
PLoS Genetics,
7(6).
Abstract:
Multiple loci are associated with white blood cell phenotypes
White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
Abstract.
Frayling TM, Ong K (2011). Piecing together the FTO jigsaw.
GENOME BIOLOGY,
12(2).
Author URL.
Frayling TM, Ong K (2011). Piecing together the FTO jigsaw.
Genome Biol,
12(2).
Abstract:
Piecing together the FTO jigsaw.
Two recent studies of the FTO gene provide more information on how it affects body mass index.
Abstract.
Author URL.
Pennell CE, Ang QW, Merialdi M, Williams S, Thorsen P, Katz M, Frayling TM, Olson D, Lye SJ, Vadillo-Ortega F, et al (2011). Preterm Birth Genome Project - Identification of Genetic Variants Associated with Spontaneous Preterm Birth.
REPRODUCTIVE SCIENCES,
18(3), 266A-266A.
Author URL.
Xie W, Frayling TM, Weedon MN (2011). Recent Progress in Identifying Genes Contributing to Type 2 Diabetes and Metabolic Syndrome. , 106-119.
Edghill EL, Khamis A, Weedon MN, Walker M, Hitman GA, McCarthy MI, Owen KR, Ellard S, T Hattersley A, Frayling TM, et al (2011). Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes.
Diabet Med,
28(6), 681-684.
Abstract:
Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes.
AIM: Genome-wide association studies have identified >30 common variants associated with Type 2 diabetes (>5% minor allele frequency). These variants have small effects on individual risk and do not account for a large proportion of the heritable component of the disease. Monogenic forms of diabetes are caused by mutations that occur in 1%. We found no difference in carrier frequency between patients (5.7%) and control subjects (5.0%) (P=0.46). There were also no differences between patients and control subjects when analyses were limited to subsets of variants. The strongest subset were those variants in the DNA binding domain where all five variants identified were only found in patients (P=0.06). CONCLUSION: Approximately 5% of UK individuals carry a PDX1 variant, but there is no evidence that these variants, either individually or cumulatively, predispose to Type 2 diabetes. Further studies will need to consider strategies to assess the role of multiple variants that occur in
Abstract.
Author URL.
Morris AP, Lindgren CM, Zeggini E, Timpson NJ, Frayling TM, Hattersley AT, McCarthy MI (2010). A powerful approach to sub-phenotype analysis in population-based genetic association studies.
Genetic Epidemiology,
34(4), 335-343.
Abstract:
A powerful approach to sub-phenotype analysis in population-based genetic association studies
The ultimate goal of genome-wide association (GWA) studies is to identify genetic variants contributing effets to complex phenotypes in order to improve our understanding of the biological architecture underlying the trait. One approach to allow us to meet this challenge is to consider more refined sub-phenotypes of disease, defined by pattern of symptoms, for example, which may be physiologically distinct, and thus may have different underlying genetic causes. The disadvantage of sub-phenotype analysis is that large disease cohorts are sub-divided into smaller case categories, thus reducing power to detect association. To address this issue, we have developed a novel test of association within a multinomial regression modeling framework, allowing for heterogeneity of genetic effects between sub-phenotypes. The modeling framework is extremely flexible, and can be generalized to any number of distinct sub-phenotypes. Simulations demonstrate the power of the multinomial regression-based analysis over existing methods when genetic effects differ between sub-phenotypes, with minimal loss of power when these effects are homogenous for the unified phenotype. Application of the multinomial regression analysis to a genome-wide association study of type 2 diabetes, with cases categorized according to body mass index, highlights previously recognized differential mechanisms underlying obese and non-obese forms of the disease, and provides evidence of a potential novel association that warrants follow-up in independent replication cohorts. © 2009 Wiley-Liss, Inc.
Abstract.
Raffiq S, Frayling T, Vyse T, Cunninghame-Graham D, Eggleton P (2010). Assessing association of common variation in the C1q gene cluster with systemic lupus erythematosus. Clinical Experimental Immunology, 161(2), 284-289.
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Mägi R, et al (2010). Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
Nature Genetics,
42(11), 937-948.
Abstract:
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
Obesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of 42 SNPs in up to 125,931 aDitional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci aSociated with body maS index (P < 5-10-8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly aSociated loci may provide new insights into human body weight regulation. © 2010 Nature America, Inc. All rights reserved.
Abstract.
Heid IM, Henneman P, Hicks A, Coassin S, Winkler T, Aulchenko YS, Fuchsberger C, Song K, Hivert MF, Waterworth DM, et al (2010). Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: Results of genome-wide association analyses including 4659 European individuals.
Atherosclerosis,
208(2), 412-420.
Abstract:
Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: Results of genome-wide association analyses including 4659 European individuals
Objective: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. Methods: We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 × 10-4 for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. Results: the ADIPOQ locus showed genome-wide significant p-values in the combined (p = 4.3 × 10-24) as well as in both women- and men-specific analyses (p = 8.7 × 10-17 and p = 2.5 × 10-11, respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p > 0.01). Conclusions: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin. © 2009 Elsevier Ireland Ltd.
Abstract.
Reiling E, Jafar-Mohammadi B, Van 'T Riet E, Weedon MN, Van Vliet-Ostaptchouk JV, Hansen T, Saxena R, Van Haeften TW, Arp PA, Das S, et al (2010). Genetic association analysis of LARS2 with type 2 diabetes.
Diabetologia,
53(1), 103-110.
Abstract:
Genetic association analysis of LARS2 with type 2 diabetes
Aims/hypothesis: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF>5%) to type 2 diabetes risk. Methods: We combined genome-wide association data (n=10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n=999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. Results: No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p=0.45, n=31,962 and OR 0.99 [0.90-1.08], p=0.78, n=35,715 respectively). Conclusions/interpretation: in this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.
Abstract.
Perry JRB, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, Sparsø T, Thorleifsson G, Grallert H, Ferrucci L, Maggio M, et al (2010). Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.
Hum Mol Genet,
19(3), 535-544.
Abstract:
Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the a allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
Abstract.
Author URL.
Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, Lyssenko V, Bouatia-Naji N, Dupuis J, Jackson AU, et al (2010). Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.
Nature Genetics,
42(2), 142-148.
Abstract:
Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, Β (s.e.m.) = 0.09 (0.01) mmol/l per a allele, P = 2.0 × 10 15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10 17; ratio of insulin to glucose area under the curve, P = 1.3 × 10 16) and diminished incretin effect (n = 804; P = 4.3 × 10 4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10 16), VPS13C (rs17271305, P = 4.1 × 10 8), GCKR (rs1260326, P = 7.1 × 10 11) and TCF7L2 (rs7903146, P = 4.2 × 10 10) associated with 2-h glucose. of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 × 10 18).
Abstract.
Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF, Giannoulatou E, et al (2010). Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
Nature,
464(7289), 713-720.
Abstract:
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.
Abstract.
Furberg H, Kim Y, Dackor J, Boerwinkle E, Franceschini N, Ardissino D, Bernardinelli L, Mannucci PM, Mauri F, Merlini PA, et al (2010). Genome-wide meta-analyses identify multiple loci associated with smoking behavior.
Nature Genetics,
42(5), 441-447.
Abstract:
Genome-wide meta-analyses identify multiple loci associated with smoking behavior
Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], Β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10 73). Two 10q25 SNPs (rs1329650[G], Β = 0.367, s.e. = 0.059, P = 5.7 × 10 10; and rs1028936[A], Β = 0.446, s.e. = 0.074, P = 1.3 × 10 9) and one 9q13 SNP in EGLN2 (rs3733829[G], Β = 0.333, s.e. = 0.058, P = 1.0 × 10 8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 × 10 8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 × 10 8) was significantly associated with smoking cessation. © 2010 Nature America, Inc. All rights reserved.
Abstract.
Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, et al (2010). Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Nature,
467(7317), 832-838.
Abstract:
Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P
Abstract.
Author URL.
Freathy RM, Hayes MG, Urbanek M, Lowe LP, Lee H, Ackerman C, Frayling TM, Cox NJ, Dunger DB, Dyer AR, et al (2010). Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: Common Genetic Variants in <i>GCK</i> and <i>TCF7L2</i> Are Associated with Fasting and Postchallenge Glucose Levels in Pregnancy and with the New Consensus Definition of Gestational Diabetes Mellitus from the International Association of Diabetes and Pregnancy Study Groups.
DIABETES,
59(10), 2682-2689.
Author URL.
Bell CG, Finer S, Lindgren CM, Wilson GA, Rakyan VK, Teschendorff AE, Akan P, Stupka E, Down TA, Prokopenko I, et al (2010). Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.
PLoS ONE,
5(11).
Abstract:
Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus
Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele a (p = 9.40×10-4, permutation p = 1.0×10-3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10-7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within diseaseassociated loci, thus providing a novel route to aid unravelling common complex diseases. © 2010 Bell et al.
Abstract.
Boraska V, Rayner NW, Groves CJ, Frayling TM, Diakite M, Rockett KA, Kwiatkowski DP, Day-Williams AG, McCarthy MI, Zeggini E, et al (2010). Large-scale association analysis of TNF/LTA gene region polymorphisms in type 2 diabetes.
BMC Medical Genetics,
11(1).
Abstract:
Large-scale association analysis of TNF/LTA gene region polymorphisms in type 2 diabetes
Background: the TNF/LTA locus has been a long-standing T2D candidate gene. Several studies have examined association of TNF/LTA SNPs with T2D but the majority have been small-scale and produced no convincing evidence of association. The purpose of this study is to examine T2D association of tag SNPs in the TNF/LTA region capturing the majority of common variation in a large-scale sample set of UK/Irish origin.Methods: This study comprised a case-control (1520 cases and 2570 control samples) and a family-based component (423 parent-offspring trios). Eleven tag SNPs (rs928815, rs909253, rs746868, rs1041981 (T60N), rs1800750, rs1800629 (G-308A), rs361525 (G-238A), rs3093662, rs3093664, rs3093665, and rs3093668) were selected across the TNF/LTA locus and genotyped using a fluorescence-based competitive allele specific assay. Quality control of the obtained genotypes was performed prior to single- and multi-point association analyses under the additive model.Results: We did not find any consistent SNP associations with T2D in the case-control or family-based datasets.Conclusions: the present study, designed to analyse a set of tag SNPs specifically selected to capture the majority of common variation in the TNF/LTA gene region, found no robust evidence for association with T2D. To investigate the presence of smaller effects of TNF/LTA gene variation with T2D, a large-scale meta-analysis will be required. © 2010 Boraska et al; licensee BioMed Central Ltd.
Abstract.
Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Ssteinthorsdottir V, Tthorleifsson G, Zillikens C, Sspeliotes EK, Mägi R, et al (2010). Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
Nature Genetics,
42(11), 949-960.
Abstract:
Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9-10-9 to P = 1.8-10-40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9-10-3 to P = 1.2-10-13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. © 2010 Nature America, Inc. All rights reserved.
Abstract.
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, et al (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Nat Genet,
42(2), 105-116.
Abstract:
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Abstract.
Author URL.
De Silva NMG, Frayling TM (2010). Novel biological insights emerging from genetic studies of type 2 diabetes and related metabolic traits.
Curr Opin Lipidol,
21(1), 44-50.
Abstract:
Novel biological insights emerging from genetic studies of type 2 diabetes and related metabolic traits.
PURPOSE OF REVIEW: in the past 3 years, genome-wide association studies have identified many tens of common genetic variants associated with metabolic diseases and traits. Although much further research is needed to identify the target genes, the associations between gene variants and diseases are already providing biological insights. The purpose of this review is to update the reader with the most relevant findings, with a particular emphasis on type 2 diabetes (T2D) and glucose metabolism, and discuss some of the biological implications of the genetic findings. RECENT FINDINGS: Largely through recent genome-wide association studies, we now know of approximately 20 gene variants associated with T2D, 10 with body mass index (BMI) and obesity, four with fasting glucose levels in the normoglycaemic population and over 30 with lipid levels. These findings are stimulating many new important areas of research related to metabolic diseases. For T2D and glucose metabolism, we discuss a number of aspects and implications of the genetic findings, including the observations that T2D gene variants are not usually in or near obvious candidate genes, highlighting the poor prior knowledge of the biology of the disease; most T2D gene variants are associated with beta-cell function rather than insulin resistance; there is a difference between genes that influence variation in normal glucose levels compared with those influencing onset and progression of diabetes; and there is a genetic link between diabetes and foetal growth. SUMMARY: Genetic studies in the past 3 years have provided a greatly increased knowledge of the regions of the genome involved in adverse metabolic consequences. There are now over 100 common genetic variants reproducibly associated with metabolic traits, including reduced beta-cell function, obesity, increased lipid levels and increased glucose levels. These genetic findings are already altering perceptions of how these traits develop and interact to result in diseases such as T2D.
Abstract.
Author URL.
Lango Allen H, Johansson S, Ellard S, Shields B, Hertel JK, Raeder H, Colclough K, Molven A, Frayling TM, Njølstad PR, et al (2010). Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes.
Diabetes,
59(1), 266-271.
Abstract:
Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes.
OBJECTIVE: Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS: Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS: We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years if present, P = 1.6 x 10(-10)) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x 10(-2)). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x 10(-4)) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x 10(-38)). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x 10(-3)). CONCLUSIONS: We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants.
Abstract.
Author URL.
Cluett C, Brayne C, Clarke R, Evans G, Matthews F, Rubinsztein DC, Huppert F, Llewellyn DJ, Rice N, Henley W, et al (2010). Polymorphisms in LMNA and near a SERPINA gene cluster are associated with cognitive function in older people.
Neurobiol Aging,
31(9), 1563-1568.
Abstract:
Polymorphisms in LMNA and near a SERPINA gene cluster are associated with cognitive function in older people.
A recent genome-wide association (GWA) study of late-onset Alzheimer's disease (LOAD) identified 15 novel single nucleotide polymorphisms (SNPs) independent of ApoE. We hypothesised that variants associated with LOAD are also associated with poor cognitive function in elderly populations. We measured additive associations between the five most strongly associated LOAD SNPs and grouped Mini Mental State Examination (MMSE) scores. Variants were genotyped in respondents (mean age 79 years) from the Oxford Healthy Ageing project (OHAP) and other sites of the MRC Cognitive Function and Ageing Study (MRC-CFAS). In adjusted ordinal logistic models, two variants were associated with poorer cognitive function: rs11622883 (OR=1.14, 95% CI: 1.01-1.28, p=0.040) and rs505058 (OR=1.29, 95% CI: 1.02-1.64, p=0.036). These SNPs are close to a SERPINA gene cluster and within LMNA, respectively. The mechanisms underlying the associations with cognitive impairment and LOAD require further elucidation, but both genes are interesting candidates for involvement in age-related cognitive impairment.
Abstract.
Author URL.
Jafar-Mohammadi B, Groves CJ, Owen KR, Frayling TM, Hattersley AT, McCarthy MI, Gloyn AL (2010). Role of low frequency variants in <i>HNF1A</i> exons 8-10 encoding hepatocyte nuclear factor-1 alpha isoform a to susceptibility to Type 2 diabetes.
IRISH JOURNAL OF MEDICAL SCIENCE,
179, 538-538.
Author URL.
Webster RJ, Warrington NM, Beilby JP, Frayling TM, Palmer LJ (2010). The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI.
BMC Medical Genetics,
11(1).
Abstract:
The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI
Background: Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI).Methods: the study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.Results: in cross-sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the a allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood.Conclusions: There was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time. © 2010 Webster et al; licensee BioMed Central Ltd.
Abstract.
Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, et al (2010). Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
Nature Genetics,
42(7), 579-589.
Abstract:
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. © 2010 Nature America, Inc. All rights reserved.
Abstract.
Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, et al (2010). Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
Nat Genet,
42(5), 430-435.
Abstract:
Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
Abstract.
Author URL.
Freathy RM, Ring SM, Shields B, Galobardes B, Knight B, Weedon MN, Smith GD, Frayling TM, Hattersley AT (2009). A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy.
Hum Mol Genet,
18(15), 2922-2927.
Abstract:
A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy.
Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes. Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some pregnant women continue to smoke. A recent genome-wide association study demonstrated an association between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy, we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds (95% CI 1.11-1.45) of continued smoking during pregnancy (P = 0.0006). Adjustment for pre-pregnancy smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03-1.39); P = 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the first, but not the last, trimester [OR for smoking 10+ cigarettes/day versus 1-9/day in first trimester = 1.30 (95% CI 1.13-1.50); P = 0.0003]. To conclude, we have found strong evidence of association between the rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the previously observed association with smoking quantity. Our data support the role of genetic factors in influencing smoking cessation during pregnancy.
Abstract.
Author URL.
Brent Richards J, Waterworth D, O'Rahilly S, Hivert MF, Loos RJF, Perry JRB, Tanaka T, Timpson NJ, Semple RK, Soranzo N, et al (2009). A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.
PLoS Genetics,
5(12).
Abstract:
A genome-wide association study reveals variants in ARL15 that influence adiponectin levels
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10-19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10-3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. © 2009 Richards et al.
Abstract.
Timpson NJ, Lindgren CM, Weedon MN, Randall J, Ouwehand WH, Strachan DP, Rayner NW, Walker M, Hitman GA, Doney ASF, et al (2009). Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.
Diabetes,
58(2), 505-510.
Abstract:
Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.
OBJECTIVE: This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS: We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into "obese" and "nonobese") according to median BMI (30.2 kg/m(2)). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS: in the "obese-type 2 diabetes" scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 x 10(-13)), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the "nonobese" scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 x 10(-14)). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: P(DIFF) = 1.4 x 10(-7); TCF7L2: P(DIFF) = 4.0 x 10(-6)). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR(obese) 1.08 [1.01-1.15]; RR(nonobese) 1.18 [1.10-1.27]: P(DIFF) = 0.04). CONCLUSIONS: This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.
Abstract.
Author URL.
Perry JRB, Ferrucci L, Bandinelli S, Guralnik J, Semba RD, Rice N, Melzer D, DIAGRAM Consortium, Saxena R, Scott LJ, et al (2009). Circulating beta-carotene levels and type 2 diabetes-cause or effect?.
Diabetologia,
52(10), 2117-2121.
Abstract:
Circulating beta-carotene levels and type 2 diabetes-cause or effect?
AIMS/HYPOTHESIS: Circulating beta-carotene levels are inversely associated with risk of type 2 diabetes, but the causal direction of this association is not certain. In this study we used a Mendelian randomisation approach to provide evidence for or against the causal role of the antioxidant vitamin beta-carotene in type 2 diabetes. METHODS: We used a common polymorphism (rs6564851) near the BCMO1 gene, which is strongly associated with circulating beta-carotene levels (p = 2 x 10(-24)), with each G allele associated with a 0.27 standard deviation increase in levels. We used data from the InCHIANTI and Uppsala Longitudinal Study of Adult Men (ULSAM) studies to estimate the association between beta-carotene levels and type 2 diabetes. We next used a triangulation approach to estimate the expected effect of rs6564851 on type 2 diabetes risk and compared this with the observed effect using data from 4549 type 2 diabetes patients and 5579 controls from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. RESULTS: a 0.27 standard deviation increase in beta-carotene levels was associated with an OR of 0.90 (95% CI 0.86-0.95) for type 2 diabetes in the InCHIANTI study. This association was similar to that of the ULSAM study (OR 0.90 [0.84-0.97]). In contrast, there was no association between rs6564851 and type 2 diabetes (OR 0.98 [0.93-1.04], p = 0.58); this effect size was also smaller than that expected, given the known associations between rs6564851 and beta-carotene levels, and the associations between beta-carotene levels and type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings in this Mendelian randomisation study are in keeping with randomised controlled trials suggesting that beta-carotene is not causally protective against type 2 diabetes.
Abstract.
Author URL.
Frayling TM (2009). Commentary: a new dawn for genetic epidemiology?.
Int J Epidemiol,
38(4), 975-977.
Author URL.
Langenberg C, Pascoe L, Mari A, Tura A, Laakso M, Frayling TM, Barroso I, Loos RJF, Wareham NJ, Walker M, et al (2009). Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response.
Diabetologia,
52(8), 1537-1542.
Abstract:
Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response
We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p∈=∈5.8∈×∈10-5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (-0.19 [-0.28, -0.10], p∈=∈1. 7∈×∈10-5), as well as with decreased beta cell glucose sensitivity (-0.11 [-0.20, -0.027], p∈=∈0.010). No associations were observed with clamp-assessed insulin sensitivity (p∈=∈0.15) or different measures of body size (p∈>∈0.7 for all). Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.
Abstract.
Murray A, Cluett C, Bandinelli S, Corsi AM, Ferrucci L, Guralnik J, Singleton A, Frayling T, Melzer D (2009). Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people.
Eur Heart J,
30(14), 1711-1719.
Abstract:
Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people.
AIMS: There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population. METHODS AND RESULTS: in the InCHIANTI Study of Aging (age >or=65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4-14, n = 594), reduced HDL (5-16, n = 635), and increased triglycerides (7-16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained
Abstract.
Author URL.
Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM (2009). Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients.
J Clin Endocrinol Metab,
94(5), 1623-1629.
Abstract:
Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients.
INTRODUCTION: Animal studies suggest that up to 80% of intracellular T(3) in the brain is derived from circulating T(4) by local deiodination. We hypothesized that in patients on T(4) common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T(4)/T(3) without necessarily affecting serum thyroid hormone levels. METHODS: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T(4)/T(3) in 552 subjects on T(4) from the Weston Area T(4) T(3) Study (WATTS). Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12). RESULTS: the rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on T(4) (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T(4)/T(3) therapy compared with T(4) only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P = 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels. CONCLUSIONS: Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T(4) and enhanced response to combination T(4)/T(3) therapy, but did not affect serum thyroid hormone levels.
Abstract.
Author URL.
Ferrucci L, Perry JRB, Matteini A, Perola M, Tanaka T, Silander K, Rice N, Melzer D, Murray A, Cluett C, et al (2009). Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.
Am J Hum Genet,
84(2), 123-133.
Abstract:
Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.
Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.
Abstract.
Author URL.
Yajnik CS, Janipalli CS, Bhaskar S, Kulkarni SR, Freathy RM, Prakash S, Mani KR, Weedon MN, Kale SD, Deshpande J, et al (2009). FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians.
Diabetologia,
52(2), 247-252.
Abstract:
FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians.
AIMS AND HYPOTHESIS: Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune. METHODS: We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals from Mysore, South India. RESULTS: We observed a strong association of the minor allele a at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13-1.40; p = 3 x 10(-5)). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01-0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09-0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06-1.37; p = 4.0 x 10(-3)), and also for waist circumference and other anthropometric variables. CONCLUSIONS: Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes.
Abstract.
Author URL.
Hennig BJ, Fulford AJ, Sirugo G, Rayco-Solon P, Hattersley AT, Frayling TM, Prentice AM (2009). FTO gene variation and measures of body mass in an African population.
BMC Med Genet,
10Abstract:
FTO gene variation and measures of body mass in an African population.
BACKGROUND: Variation in the fat mass and obesity associated (FTO) gene has been reproducibly associated with body mass index (BMI) and obesity in populations of White European origin. Data from Asians and African-Americans is less conclusive. METHODS: We assessed the effect of 16 FTO polymorphisms on body mass in a large population of predominantly lean Gambians (N(max) 2208) participating in a long-term surveillance program providing contemporary and early-life anthropometric measurements. RESULTS: Sixteen FTO tagSNPs screened here, including several associated with BMI in Europeans, were not associated with birth weight (BWT), early weight gain in 1-2 year olds, BMI in adults (> or = 18 y), or weight-for-height (WFH) z-score across all ages. No association was seen between genotype and WFH z-score or other measures of body mass. The confidence limits indicate that the effect size for WFH z-score never exceeded 0.17 units per allele copy for any SNP (excluding the three SNPs with allele < 15%). with much the lowest allele frequency. The confidence interval of the effect size for rs9939609 did not overlap that reported previously in Europeans. CONCLUSION: to our knowledge this is the first study of FTO gene variation in a well-characterised African population. Our results suggest that FTO gene variation does not influence measures of body mass in Gambians living a traditional lifestyle, or has a smaller effect than that detected in Europeans. These findings are not directly comparable to results from previous studies in African-Americans due to differences in study design and analysis. It is also possible that any effect of FTO genotype on body mass is of limited relevance in a lean population where little excess food is available, compared to similar ethnic populations where food supply is plentiful.
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Author URL.
Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L, Speliotes EK, Thorleifsson G, Willer CJ, Herrera BM, et al (2009). Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution.
PLoS Genetics,
5(6).
Abstract:
Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×102 -11) and MSRA (WC, P = 8.9×10-9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10 -8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Abstract.
Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, Najjar SS, Zhao JH, Heath SC, Eyheramendy S, et al (2009). Genome-wide association study identifies eight loci associated with blood pressure.
Nature Genetics,
41(6), 666-676.
Abstract:
Genome-wide association study identifies eight loci associated with blood pressure
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
Abstract.
Thomas K, Rafiq S, Frayling TM, Ebrahim S, Kumari M, Gallacher J, Ferrucci L, Bandinelli S, Wallace RB, Melzer D, et al (2009). Interleukin-18 polymorphism and physical functioning in older people: a replication study and meta-analysis.
J Gerontol a Biol Sci Med Sci,
64(11), 1177-1182.
Abstract:
Interleukin-18 polymorphism and physical functioning in older people: a replication study and meta-analysis.
BACKGROUND: Levels of the proinflammatory cytokine interleukin-18 (IL-18) are raised in old age and are associated with reduced physical functioning. Previous studies have indicated that the C allele of the rs5744256 polymorphism in the IL-18 gene is strongly associated with reduced circulating IL-18 levels. This variant has previously been associated with improved locomotor performance in old age, but the finding requires independent replication. METHODS: We examined the association between the IL-18 polymorphism rs5744256 and physical functioning in three cohorts with a total of 4,107 participants aged 60-85 years: the English Longitudinal Study of Ageing, Caerphilly, and Boyd Orr. We meta-analyzed (N = 6,141) the results with data from the original paper reporting this association: Iowa-Established Populations for Epidemiological Study of the Elderly and InCHIANTI cohorts. Physical functioning was assessed by timed walks or the get up and go test. As locomotor performance tests differed between the cohorts and the distributions of times to complete the test (in seconds) were positively skewed, we used the reciprocal transformation and computed study-specific z scores. RESULTS: Based on the three new studies, the estimated linear regression coefficient per C allele was 0.011 (95% confidence interval [95% CI]: -0.04 to 0.06). A meta-analysis that pooled the data from all studies showed weak evidence of an effect, with a regression coefficient of 0.047 (95% CI: 0.010 to 0.083). CONCLUSIONS: We did not replicate an association between the IL-18 rs5744256 polymorphism and the physical function in people aged 60-85 years. However, pooling data from all studies suggested a weak association of the C allele of the rs5744256 single nucleotide polymorphism on improving walking times in old age.
Abstract.
Author URL.
Perry JRB, McCarthy MI, Hattersley AT, Zeggini E, Wellcome Trust Case Control Consortium, Weedon MN, Frayling TM (2009). Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach.
Diabetes,
58(6), 1463-1467.
Abstract:
Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach.
OBJECTIVE: Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS: We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases. RESULTS: After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top P(adj) = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas. CONCLUSIONS: Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more successful for some complex traits than others, depending on the nature of the underlying disease physiology.
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Author URL.
Southam L, Soranzo N, Montgomery SB, Frayling TM, McCarthy MI, Barroso I, Zeggini E (2009). Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants?.
Diabetologia,
52(9), 1846-1851.
Abstract:
Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants?
Aims/hypothesis: According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci. Methods: We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F ST) for 17 type 2 diabetes and 13 obesity loci. Results: We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F ST for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date. Conclusions/interpretation: Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues. © 2009 Springer-Verlag.
Abstract.
Prokopenko I, Zeggini E, Hanson RL, Mitchell BD, Rayner NW, Akan P, Baier L, Das SK, Elliott KS, Fu M, et al (2009). Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
Diabetes,
58(7), 1704-1709.
Abstract:
Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
OBJECTIVE: Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. RESEARCH DESIGN AND METHODS: in all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate approximately 80% coverage of common variation across the region (r (2) > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in approximately 8,500 case subjects and 12,400 control subjects. RESULTS: Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21-1.57], P = 1.4 x 10(-6), in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18-1.76], P = 1.0 x 10(-5), under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. CONCLUSIONS: Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.
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Author URL.
Jafar-Mohammadi B, Groves CJ, Owen KR, Frayling TM, Hattersley AT, McCarthy MI, Gloyn AL (2009). Low Frequency Variants in the Exons Only Encoding Isoform a of <i>HNF1A</i> Do Not Contribute to Susceptibility to Type 2 Diabetes.
PLOS ONE,
4(8).
Author URL.
Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S, Jonasdottir A, Sigurdsson A, Kristinsson KT, Jonasdottir A, et al (2009). Parental origin of sequence variants associated with complex diseases.
Nature,
462(7275), 868-874.
Abstract:
Parental origin of sequence variants associated with complex diseases
Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Fiveone with breast cancer, one with basal-cell carcinoma and three with type 2 diabeteshave parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. © 2009 Macmillan Publishers Limited. All rights reserved.
Abstract.
Shields BM, Freathy RM, Knight BA, Hill A, Weedon MN, Frayling TM, Hattersley AT, Vaidya B (2009). Phosphodiesterase 8B gene polymorphism is associated with subclinical hypothyroidism in pregnancy.
J Clin Endocrinol Metab,
94(11), 4608-4612.
Abstract:
Phosphodiesterase 8B gene polymorphism is associated with subclinical hypothyroidism in pregnancy.
BACKGROUND: Maternal subclinical hypothyroidism is associated with a number of adverse outcomes in pregnancy. The Endocrine Society's recent consensus guidelines have recommended treatment with T(4) for this condition in pregnancy. The single nucleotide polymorphism rs4704397 in the phosphodiesterase 8B (PDE8B) gene has been found to be associated with altered serum TSH concentrations in the general population. We aimed to assess whether genetic variation in TSH due to the rs4704397 genotype affects the number of individuals classified as having subclinical hypothyroidism in pregnancy. METHODS: Serum TSH, FT4, FT3, and thyroid peroxidase antibodies (TPOAbs) were measured in 970 pregnant women at 28 wk gestation. rs4704397 genotype was available on 877 subjects. Reference range calculations were based on the TPOAb-negative women. RESULTS: TSH, but not FT4, FT3, or TPOAbs, varied with genotype and was highest in those with the AA genotype (median, 2.16, 1.84, and 1.73 mIU/liter for AA, AG, and GG genotypes, respectively; P = 0.0004). A greater proportion of women with the AA genotype had TSH concentrations above 4.21 mIU/liter, the upper limit of the reference range, compared with the AG and GG genotypes (9.6 vs. 3.5%, respectively; P = 0.004). Maternal PDE8B genotype was not associated with offspring birthweight or gestational age at delivery. CONCLUSION: Genetic variation in TSH levels in pregnancy associated with the PDE8B rs4704397 genotype has implications for the number of women treated for subclinical hypothyroidism under current guidelines. Consideration should be made to individualization of normal ranges, potential effects on pregnancy outcome, and intention to treat for subclinical hypothyroidism in pregnancy.
Abstract.
Author URL.
Perry JRB, Weedon MN, Frayling TM (2009). Response to comment on: Perry et al. (2009) Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach. Diabetes;58:1463-1467. Diabetes, 58(9).
Willer CJ, Speliotes EK, Loos RJF, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, et al (2009). Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.
Nat Genet,
41(1), 25-34.
Abstract:
Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.
Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
Abstract.
Author URL.
Cluett C, McDermott MM, Guralnik J, Ferrucci L, Bandinelli S, Miljkovic I, Zmuda JM, Li R, Tranah G, Harris T, et al (2009). The 9p21 myocardial infarction risk allele increases risk of peripheral artery disease in older people.
Circ Cardiovasc Genet,
2(4), 347-353.
Abstract:
The 9p21 myocardial infarction risk allele increases risk of peripheral artery disease in older people.
BACKGROUND: a common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single-nucleotide polymorphism) is strongly associated with myocardial infarction and major arterial aneurysms. An association with peripheral arterial disease (PAD) was also reported in a sample younger than 75 years, but this disappeared on removal of respondents with a myocardial infarction history, resulting in an odds ratio of 1.09 for PAD (P=0.075). We aimed at estimating the association of this variant with an Ankle-Brachial Index (ABI) and PAD in 3 older populations. METHODS AND RESULTS: We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging, and Health, Aging, and Body Composition studies. In 2630 white individuals (mean age, 76.4 years), the C allele at rs1333049 was associated with lower mean ABI measures and with an increased prevalence of PAD. These associations remained after removal of baseline and incident myocardial infarction cases over a 6-year follow-up for both ABI (-0.017 ABI units; 95% CI, -0.03 to -0.01; P = 1.3 x 10(-4)) and PAD (per allele odds ratio, 1.29; 95% CI, 1.06 to 1.56; P = 0.012). These associations also remained after adjustment for known atherosclerosis risk factors, including diabetes mellitus, smoking, hypercholesterolemia, and hypertension. CONCLUSIONS: the C allele at rs1333049 is associated with an increased prevalence of PAD and lower mean ABI. This association was independent of the presence of diagnosed myocardial infarction and atherosclerotic risk factors in 3 older white populations.
Abstract.
Author URL.
Webster RJ, Warrington NM, Weedon MN, Hattersley AT, McCaskie PA, Beilby JP, Palmer LJ, Frayling TM (2009). The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits.
Diabetologia,
52(1), 106-114.
Abstract:
The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits.
AIMS/HYPOTHESIS: Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. METHODS: the individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS: the findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the a allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007). CONCLUSIONS/INTERPRETATION: the current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.
Abstract.
Author URL.
Rice NE, Bandinelli S, Corsi AM, Ferrucci L, Guralnik JM, Miller MA, Kumari M, Murray A, Frayling TM, Melzer D, et al (2009). The paraoxonase (PON1) Q192R polymorphism is not associated with poor health status or depression in the ELSA or INCHIANTI studies.
Int J Epidemiol,
38(5), 1374-1379.
Abstract:
The paraoxonase (PON1) Q192R polymorphism is not associated with poor health status or depression in the ELSA or INCHIANTI studies.
BACKGROUND: the human paraoxonase (PON1) protein detoxifies certain organophosphates, and the PON1 Q192R polymorphism (rs662) affects PON1 activity. Groups with higher dose exposure to organophosphate sheep dips or first Gulf War nerve toxins reported poorer health if they had 192R, and these associations have been used to exemplify Mendelian randomization analysis. However, a reported association of 192R with depression in a population-based study of older women recently cast doubt on the specificity of the higher dose findings. We aimed to examine associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent population-based studies. METHODS: We used logistic regression models to examine the associations in men and women aged 60-79 years from the English Longitudinal Study of Ageing (ELSA, n = 3158) and InCHIANTI (n = 761) population studies. Outcomes included the Center for Epidemiologic Studies Depression (CES-D) scale, self-rated general health status and (in ELSA only) diagnoses of depression. RESULTS: the PON1 Q192R polymorphism was not associated with self-reported poor health {meta-analysis: odds ratio (OR) = 1.01 [confidence interval (CI) 0.91-1.13], P = 0.80} or depressive symptoms in either study or in meta-analyses [CES-D: OR = 1.01 (CI 0.87-1.17), P = 0.90]. There was also no association with histories of diagnosed depression in ELSA [OR = 1.03 (CI 0.82-1.30), P = 0.80]. CONCLUSIONS: We found no evidence of an association between the PON1 Q192R polymorphism and poor general or mental health in two independent population-based studies. Neither the claimed Q192R association with depression in the general population nor its theoretical implications were supported.
Abstract.
Author URL.
Freathy RM, Bennett AJ, Ring SM, Shields B, Groves CJ, Timpson NJ, Weedon MN, Zeggini E, Lindgren CM, Lango H, et al (2009). Type 2 diabetes risk alleles are associated with reduced size at birth.
Diabetes,
58(6), 1428-1433.
Abstract:
Type 2 diabetes risk alleles are associated with reduced size at birth.
OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
Abstract.
Author URL.
Salanti G, Southam L, Altshuler D, Ardlie K, Barroso I, Boehnke M, Cornelis MC, Frayling TM, Grallert H, Grarup N, et al (2009). Underlying genetic models of inheritance in established type 2 diabetes associations.
American Journal of Epidemiology,
170(5), 537-545.
Abstract:
Underlying genetic models of inheritance in established type 2 diabetes associations
For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed-or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.
Abstract.
Panicker V, Cluett C, Shields B, Murray A, Parnell KS, Perry JRB, Weedon MN, Singleton A, Hernandez D, Evans J, et al (2008). A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine.
J Clin Endocrinol Metab,
93(8), 3075-3081.
Abstract:
A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine.
INTRODUCTION: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. METHODS: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. RESULTS: a SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. CONCLUSIONS: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.
Abstract.
Author URL.
Frayling TM, Colhoun H, Florez JC (2008). A genetic link between type 2 diabetes and prostate cancer.
Diabetologia,
51(10), 1757-1760.
Abstract:
A genetic link between type 2 diabetes and prostate cancer.
Epidemiological studies suggest that men with type 2 diabetes are less likely than non-diabetic men to develop prostate cancer. The cause of this association is not known. Recent genetic studies have highlighted a potential genetic link between the two diseases. Two studies have identified a version (allele) of a variant in the HNF1B (also known as TCF2) gene that predisposes to type 2 diabetes, and one of them showed that the same allele protects men from prostate cancer. Other, separate, studies have identified different variants in the JAZF1 gene, one associated with type 2 diabetes, another associated with prostate cancer. These findings are unlikely to completely explain the epidemiological association between the two diseases but they provide new insight into a possible direct causal link, rather than one that is confounded or biased in some way.
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Author URL.
Melzer D, Perry JRB, Hernandez D, Corsi A-M, Stevens K, Rafferty I, Lauretani F, Murray A, Gibbs JR, Paolisso G, et al (2008). A genome-wide association study identifies protein quantitative trait loci (pQTLs).
PLoS Genet,
4(5).
Abstract:
A genome-wide association study identifies protein quantitative trait loci (pQTLs).
There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.
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Author URL.
Lango H, UK Type 2 Diabetes Genetics Consortium, Palmer CNA, Morris AD, Zeggini E, Hattersley AT, McCarthy MI, Frayling TM, Weedon MN (2008). Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk.
Diabetes,
57(11), 3129-3135.
Abstract:
Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk.
OBJECTIVES: Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes. A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here, we assess the ability of 18 confirmed type 2 diabetes variants to differentiate between type 2 diabetic case and control subjects. RESEARCH DESIGN AND METHODS: We assessed index single nucleotide polymorphisms (SNPs) for the 18 independent loci in 2,598 control subjects and 2,309 case subjects from the Genetics of Diabetes Audit and Research Tayside Study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of type 2 diabetes and by calculating the area under the receiver-operator characteristic curve (AUC). RESULTS: Individuals carrying more risk alleles had a higher risk of type 2 diabetes. For example, 1.2% of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI 2.11-8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI, and sex was 0.78, and adding the genetic risk variants only marginally increased this to 0.80. CONCLUSIONS: Currently, common risk variants for type 2 diabetes do not provide strong predictive value at a population level. However, the joint effect of risk variants identified subgroups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing.
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Author URL.
Pascoe L, Frayling TM, Weedon MN, Mari A, Tura A, Ferrannini E, Walker M, RISC Consortium (2008). Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles.
Diabetologia,
51(11), 1989-1992.
Abstract:
Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles.
AIMS/HYPOTHESIS: Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. METHODS: a total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. RESULTS: the diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min(-1) m(-2) (mmol/l)(-1), p = 1.51 x 10(-6)). The same was seen for the 30 min insulin response (p = 4.17 x 10(-7)). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p < 0.001 and p = 0.003, respectively). CONCLUSIONS/INTERPRETATION: This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals.
Abstract.
Author URL.
Frayling TM (2008). Commentary: Genetic association studies see light at the end of the tunnel.
Int J Epidemiol,
37(1), 133-135.
Author URL.
Loos RJF, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, et al (2008). Common variants near MC4R are associated with fat mass, weight and risk of obesity.
Nat Genet,
40(6), 768-775.
Abstract:
Common variants near MC4R are associated with fat mass, weight and risk of obesity.
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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Author URL.
Freathy RM, Timpson NJ, Lawlor DA, Pouta A, Ben-Shlomo Y, Ruokonen A, Ebrahim S, Shields B, Zeggini E, Weedon MN, et al (2008). Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.
Diabetes,
57(5), 1419-1426.
Abstract:
Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.
OBJECTIVE: Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. RESEARCH DESIGN AND METHODS: We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations. RESULTS: Each copy of the FTO rs9939609 a allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.048]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)). CONCLUSIONS: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.
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Author URL.
Lawlor DA, Timpson NJ, Harbord RM, Leary S, Ness A, McCarthy MI, Frayling TM, Hattersley AT, Smith GD (2008). Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable.
PLoS Medicine,
5(3), 0484-0493.
Abstract:
Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable
Background: the developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis. Methods and Findings: We explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)-determined fat mass measured at 9 to 11 y (4,091 parent-offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was -0.08 (95% CI: -0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17). Conclusions: Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic. © 2008 Lawlor et al.
Abstract.
Lawlor DA, Timpson NJ, Harbord RM, Leary S, Ness A, McCarthy MI, Frayling TM, Hattersley AT, Smith GD (2008). Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable.
PLoS Med,
5(3).
Abstract:
Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable.
BACKGROUND: the developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis. METHODS AND FINDINGS: We explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)-determined fat mass measured at 9 to 11 y (4,091 parent-offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was -0.08 (95% CI: -0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17). CONCLUSIONS: Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.
Abstract.
Author URL.
Rice NE, Patel BD, Lang IA, Kumari M, Frayling TM, Murray A, Melzer D (2008). Filaggrin gene mutations are associated with asthma and eczema in later life.
J Allergy Clin Immunol,
122(4), 834-836.
Author URL.
Melzer D, Ferrucci L, Singleton A, Guralnik JM, Murray A, Bandinelli S, Corsi A, Frayling T, Bandinelli S (2008). GENETIC VARIATION AND RESILIENCE IN HUMAN AGING: THE SAGA STUDY.
GERONTOLOGIST,
48, 1-1.
Author URL.
Rafiq S, Melzer D, Weedon MN, Lango H, Saxena R, Scott LJ, DIAGRAM Consortium, Palmer CNA, Morris AD, McCarthy MI, et al (2008). Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes.
Diabetologia,
51(12), 2205-2213.
Abstract:
Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes.
AIMS/HYPOTHESIS: There are strong associations between measures of inflammation and type 2 diabetes, but the causal directions of these associations are not known. We tested the hypothesis that common gene variants known to alter circulating levels of inflammatory proteins, or known to alter autoimmune-related disease risk, influence type 2 diabetes risk. METHODS: We selected 46 variants: (1) eight variants known to alter circulating levels of inflammatory proteins, including those in the IL18, IL1RN, IL6R, MIF, PAI1 (also known as SERPINE1) and CRP genes; and (2) 38 variants known to predispose to autoimmune diseases, including type 1 diabetes. We tested the associations of these variants with type 2 diabetes using a meta-analysis of 4,107 cases and 5,187 controls from the Wellcome Trust Case Control Consortium, the Diabetes Genetics Initiative, and the Finland-United States Investigation of NIDDM studies. We followed up associated variants (p < 0.01) in a further set of 3,125 cases and 3,596 controls from the UK. RESULTS: We found no evidence that inflammatory or autoimmune disease variants are associated with type 2 diabetes (at p
Abstract.
Author URL.
Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JRB, Stevens S, Hall AS, et al (2008). Genome-wide association analysis identifies 20 loci that influence adult height.
Nat Genet,
40(5), 575-583.
Abstract:
Genome-wide association analysis identifies 20 loci that influence adult height.
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.
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Author URL.
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PIW, Abecasis GR, Almgren P, Andersen G, et al (2008). Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
Nat Genet,
40(5), 638-645.
Abstract:
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
Abstract.
Author URL.
Perry JRB, Frayling TM (2008). New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function.
Curr Opin Clin Nutr Metab Care,
11(4), 371-377.
Abstract:
New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function.
PURPOSE OF REVIEW: over the past 18 months, the number of gene loci robustly associated with type 2 diabetes has risen from three to 18. In this study, we focus on explaining the genome-wide approach that has led to most of these discoveries and discuss some of the early insights the new gene loci have provided into the aetiology of type 2 diabetes. RECENT FINDINGS: Recent genome-wide association studies have provided an important resource for furthering our understanding of type 2 diabetes disease mechanisms. Genes previously unsuspected of playing a role in diabetes are now implicated in the disease process. These include genes in cell cycling control (CDKN2A/2B, CDKAL1), transcription factors (TCF7L2, HHEX), and ion channels (SLC30A8). These variants are all associated with insulin-secretory defects in the general population and show little if any relationship to insulin resistance. Two common variants (near or in FTO and MC4R) alter diabetes risk through a primary effect on obesity. SUMMARY: Recent genome-wide association studies show that there are now 18 gene loci associated with the risk of type 2 diabetes. Most of these T2D gene loci affect insulin secretion.
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Yuan X, Waterworth D, Perry JRB, Lim N, Song K, Chambers JC, Zhang W, Vollenweider P, Stirnadel H, Johnson T, et al (2008). Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.
Am J Hum Genet,
83(4), 520-528.
Abstract:
Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.
Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.
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Barroso I, Luan J, Wheeler E, Whittaker P, Wasson J, Zeggini E, Weedon MN, Hunt S, Venkatesh R, Frayling TM, et al (2008). Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies.
Diabetes,
57(11), 3161-3165.
Abstract:
Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies.
OBJECTIVE: Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS: Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS: Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x 10(-6)). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] approximately 1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). CONCLUSIONS: These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations.
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Author URL.
Weedon MN, Frayling TM (2008). Reaching new heights: insights into the genetics of human stature.
Trends Genet,
24(12), 595-603.
Abstract:
Reaching new heights: insights into the genetics of human stature.
Human height is a highly heritable, classic polygenic trait. Until recently, there had been limited success in identifying the specific genetic variants that explain normal variation of human height. The advent of large-scale genome-wide association studies, however, has led to dramatic progress. In the past 18 months, the first robust common variant associations were identified and there are now 44 loci known to influence normal variation of height. In this review, we summarize this exciting recent progress, discuss implicated biological pathways, the overlap with monogenic growth and skeletal dysplasia syndromes, links to disease and insights into the genetic architecture of this model polygenic trait. We also discuss the strong probability of finding several hundred more such loci in the near future.
Abstract.
Author URL.
Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, Davey Smith G (2008). The fat mass- and obesity-associated locus and dietary intake in children.
Am J Clin Nutr,
88(4), 971-978.
Abstract:
The fat mass- and obesity-associated locus and dietary intake in children.
BACKGROUND: a region of chromosome 16 containing the fat mass-and obesity-associated gene (FTO) is reproducibly associated with fat mass and body mass index (BMI), risk of obesity, and adiposity. OBJECTIVES: We aimed to assess the possibility that appetite plays a role in the association between FTO and BMI. DESIGN: Detailed dietary report information from the Avon Longitudinal Study of Parents and Children allowed the exploration of relations between FTO variation and dietary intake. Analyses were performed to investigate possible associations between variation at the FTO locus and the intake of a range of micronutrients and macronutrients, with adjustment for the bias often found within dietary report data when factors related to BMI are assessed. To test the hypothesis that FTO may be influencing appetite directly, rather than indirectly via BMI and altered intake requirements, we also assessed associations between FTO and dietary intake independent of BMI. RESULTS: Relations between a single-nucleotide polymorphism characterizing the FTO signal (rs9939609) and dietary variables were found and can be summarized by the effect of each additional allele (per-allele effects) on total energy and total fat (P < 0.001 for both). These associations were attenuated, but they persisted specifically for fat and energy consumption after adjustment for BMI [total daily fat consumption: approximately 1.5 g/d (P = 0.02 for the per-allele difference); total daily energy consumption: approximately 25 kJ/d (P = 0.03 for the per-allele difference)]. CONCLUSION: These associations suggest that persons carrying minor variants at rs9939609 were consuming more fat and total energy than were those not carrying such variants. They also suggest that this difference was not simply dependent on having higher average BMIs among the former group.
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Author URL.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JRB, Elliott KS, Lango H, Rayner NW, et al (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
Science,
316(5826), 889-894.
Abstract:
A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
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Author URL.
Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JRB, Elliott KS, Hackett R, Guiducci C, Shields B, et al (2007). A common variant of HMGA2 is associated with adult and childhood height in the general population.
Nat Genet,
39(10), 1245-1250.
Abstract:
A common variant of HMGA2 is associated with adult and childhood height in the general population.
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 x 10(-11), overall P = 4 x 10(-16), including the genome-wide association data). We also observed the association in children (P = 1 x 10(-6), N = 6,827) and a tall/short case-control study (P = 4 x 10(-6), N = 3,207). We estimate that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.
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Author URL.
Rafiq S, Frayling TM, Murray A, Hurst A, Stevens K, Weedon MN, Henley W, Ferrucci L, Bandinelli S, Corsi A-M, et al (2007). A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects.
Genes Immun,
8(7), 552-559.
Abstract:
A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects.
Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r(2)=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13-140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35-71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 x 10(-62). The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 x 10(-4)). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.
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Author URL.
Melzer D, Frayling TM, Murray A, Hurst AJ, Harries LW, Song H, Khaw K, Luben R, Surtees PG, Bandinelli SS, et al (2007). A common variant of the p16(INK4a) genetic region is associated with physical function in older people.
Mech Ageing Dev,
128(5-6), 370-377.
Abstract:
A common variant of the p16(INK4a) genetic region is associated with physical function in older people.
p16(INK4a) is active in cell senescence, ageing and tumor suppression. Deletion of the small p16(INK4a)/ARF/p15(INK4b) region occurs in many cancers. We screened 25 common polymorphisms across the region and three related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16(INK4a)/ARF locus and p15(INK4b)) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk samples (p-value=0.013, total n=2257), and on independent replication in the InCHIANTI study (n=709, p=0.015), and at one-sided significance in Iowa-EPESE (n=419, p=0.079). Overall (n=3372), the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele odds ratio=1.48, 95% CI: 1.17-1.88, p=0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR=1.45, 95% CI: 1.09-1.92, p=0.010, n=2434). These findings require further replication, but provide the first direct evidence that the p16(INK4a)/ARF/p15(INK4b) genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence.
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Author URL.
Frayling TM (2007). A new era in finding Type 2 diabetes genes-the unusual suspects.
Diabet Med,
24(7), 696-701.
Abstract:
A new era in finding Type 2 diabetes genes-the unusual suspects.
In 1988 the task of identifying Type 2 diabetes genes was described as a nightmare. For the next 17 years this proved to be largely correct. In the meantime the prevalence of Type 2 diabetes rose sharply due to non-genetic factors, compounding the problem of trying to find genes. Despite a huge amount of effort, progress was disappointing and only two genes, PPARG and KCNJ11, were confirmed beyond doubt as Type 2 diabetes risk factors in multiple studies. The reasons for this have been well documented and mainly consist of the use of inappropriate levels of statistical inference given the many hundreds of thousands of potential risk polymorphisms in the genome and their small effect sizes. The good news is that these problems are now surmountable and prospects for finding many more genes are bright. This year saw the identification of a third gene, TCF7L2, that has a greater impact on risk than the first two and provided important lessons for Type 2 diabetes genetic studies. The most important of these lessons was that previously unsuspected genes may be involved. In this review I discuss why this year is the start of a new era in our understanding of Type 2 diabetes genes and how this may lead to improved patient care.
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Author URL.
Frayling TM, Rafiq S, Murray A, Hurst AJ, Weedon MN, Henley W, Bandinelli S, Corsi A-M, Ferrucci L, Guralnik JM, et al (2007). An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people.
J Gerontol a Biol Sci Med Sci,
62(1), 73-78.
Abstract:
An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people.
BACKGROUND: the proinflammatory cytokine interleukin-18 (IL-18) is associated with major disabling conditions, although whether as byproduct or driver is unclear. The role of common variation in the IL-18 gene on serum concentrations and functioning in old age is unknown. METHODS: We used 1671 participants aged 65-80 years from two studies: the InCHIANTI study and wave 6 of the Iowa-Established Populations for Epidemiological Study of the Elderly (EPESE). We tested three common polymorphisms against IL-18 concentration and measures of functioning. RESULTS: in the InCHIANTI study, a 1 standard deviation increase in serum IL-18 concentrations was associated with an increased chance of being in the 20% of slowest walkers (odds ratio 1.45; 95% confidence interval, 1.17-1.80; p =.0007) and 20% of those with poorest function based on the Short Physical Performance Battery Score (odds ratio 1.52; 95% confidence interval, 1.22-1.89; p =.00016) in age sex adjusted logistic regression models. There was no association with Activities of Daily Living (p =.26) or Mini-Mental State Examination score (p =.66). The C allele of the IL-18 polymorphism rs5744256 reduced serum concentrations of IL-18 by 39 pmol/mL per allele (p =.00001). The rs5744256 single nucleotide polymorphism was also associated with shorter walk times in InCHIANTI (n = 662, p =.016) and Iowa-EPESE (n = 995, p =.026). In pooled ranked models rs5744256 was also associated with higher SPPB scores (n = 1671, p =.019). Instead of adjusting for confounders in the IL-18 walk time association, we used rs5744256 in a Mendelian randomization analysis: the association remained in instrumental variable models (p =.021). CONCLUSION: IL-18 concentrations are associated with physical function in 65- to 80-year-olds. A polymorphism in the IL-18 gene alters IL-18 concentrations and is associated with an improvement in walk speed. IL-18 may play an active role in age-related functional impairment, but these findings need independent replication.
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Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, et al (2007). Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
Nat Genet,
39(11), 1329-1337.
Abstract:
Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
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Rafiq S, Stevens K, Hurst AJ, Murray A, Henley W, Weedon MN, Bandinelli S, Corsi AM, Guralnik JM, Ferruci L, et al (2007). Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels.
Genes Immun,
8(4), 344-351.
Abstract:
Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels.
Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016-4.9 x 10(-5)). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r(2)=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r(2)=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1beta (P=0.03) level and may also be associated with interferon -gamma (P=0.03), alpha-2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.
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Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, Lango H, Frayling TM, Neumann RJ, Sherva R, et al (2007). Common variants in WFS1 confer risk of type 2 diabetes.
Nat Genet,
39(8), 951-953.
Abstract:
Common variants in WFS1 confer risk of type 2 diabetes.
We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.
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Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, Frayling TM, Yajnik CS (2007). Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population.
Diabetologia,
50(1), 63-67.
Abstract:
Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population.
AIMS AND HYPOTHESIS: India has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood. Common non-coding variants in the transcription factor 7-like 2 gene (TCF7L2) have recently been strongly associated with increased risk of type 2 diabetes in European populations. We investigated whether TCF7L2 variants are also associated with type 2 diabetes mellitus in the Indian population. MATERIALS AND METHODS: We genotyped type 2 diabetes patients (n = 955) and ethnically matched control subjects (n = 399) by sequencing three single nucleotide polymorphisms (SNPs) (rs7903146, rs12255372 and rs4506565) in TCF7L2. RESULTS: We observed a strong association with all the polymorphisms, including rs12255372 (odds ratio [OR] 1.50 [95% CI = 1.24-1.82], p = 4.0 x 10(-5)), rs4506565 (OR 1.48 [95% CI = 1.24-1.77], p = 2.0 x 10(-5)) and rs7903146 (OR 1.46 [95% CI = 1.22-1.75], p = 3.0 x 10(-5)). All three variants showed increased relative risk when homozygous rather than heterozygous, with the strongest risk for rs12255372 (OR 2.28 [95% CI = 1.40-3.72] vs OR 1.43 [95% CI = 1.11-1.83]). We found no association of the TCF7L2 genotypes with age at diagnosis, BMI or WHR, but the risk genotype at rs12255372 was associated with higher fasting plasma glucose (p = 0.001), higher 2-h plasma glucose (p = 0.0002) and higher homeostasis model assessment of insulin resistance (HOMA-R; p = 0.012) in non-diabetic subjects. CONCLUSIONS: Our study in Indian subjects replicates the strong association of TCF7L2 variants with type 2 diabetes in other populations. It also provides evidence that variations in TCF7L2 may play a crucial role in the pathogenesis of type 2 diabetes by influencing both insulin secretion and insulin resistance. TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity.
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Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, et al (2007). Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function.
Diabetes,
56(12), 3101-3104.
Abstract:
Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function.
OBJECTIVE: Type 2 diabetes is characterized by impaired pancreatic beta-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, HHEX/IDE, and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of beta-cell function and whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS: a total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of beta-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center. RESULTS: CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic beta-cell glucose sensitivity (P = 9.86 x 10(-5) and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity. CONCLUSIONS: CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic beta-cell function, including decreased beta-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity.
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Owen KR, Groves CJ, Hanson RL, Knowler WC, Shuldiner AR, Elbein SC, Mitchell BD, Froguel P, Ng MCY, Chan JC, et al (2007). Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjects.
Diabetes,
56(3), 879-883.
Abstract:
Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjects.
Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001).
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Winckler W, Weedon MN, Graham RR, McCarroll SA, Purcell S, Almgren P, Tuomi T, Gaudet D, Boström KB, Walker M, et al (2007). Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes.
Diabetes,
56(3), 685-693.
Abstract:
Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes.
An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value
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Frayling TM, McCarthy MI (2007). Genetic studies of diabetes following the advent of the genome-wide association study: where do we go from here?.
Diabetologia,
50(11), 2229-2233.
Author URL.
Melzer D, Hurst AJ, Frayling T (2007). Genetic variation and human aging: progress and prospects.
J Gerontol a Biol Sci Med Sci,
62(3), 301-307.
Abstract:
Genetic variation and human aging: progress and prospects.
The genetics of aging has seen extraordinary progress over the last few decades, with animal models suggesting key roles for a number of metabolic pathways. However, humans outlive laboratory models many times over, and only evidence from humans can ultimately identify the drivers of human aging. In this article we thematically review progress in identifying human genetic variants associated with longevity. We also look at the bigger picture of progress in identifying genetic associates of disease and functioning and healthy aging in older people. Although much of the existing evidence is fragmentary, recent exciting findings and robust methods are taking the field rapidly forward.
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Frayling TM (2007). Genome-wide association studies provide new insights into type 2 diabetes aetiology.
Nat Rev Genet,
8(9), 657-662.
Abstract:
Genome-wide association studies provide new insights into type 2 diabetes aetiology.
Human geneticists are currently in the middle of a race. Thanks to a new technology in the form of 'genome-wide chips', investigators can potentially find many novel disease genes in one large experiment. Type 2 diabetes has been hot out of the blocks with six recent publications that together provide convincing evidence for six new gene regions involved in the condition. Together with candidate approaches, these studies have identified 11 confirmed genomic regions that alter the risk of type 2 diabetes in the European population. One of these regions, the fat mass and obesity associated gene (FTO), represents by far the best example of an association between common variation and fat mass in the general population.
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Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, et al (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
NATURE,
447(7145), 661-678.
Author URL.
Weedon MN, Frayling TM (2007). Insights on pathogenesis of type 2 diabetes from MODY genetics.
Curr Diab Rep,
7(2), 131-138.
Abstract:
Insights on pathogenesis of type 2 diabetes from MODY genetics.
Maturity-onset diabetes of the young (MODY) is a type of non-insulin-dependent diabetes mellitus caused by rare autosomal-dominant mutations. MODY genes play key biochemical roles in the pancreatic beta cell; therefore, common variants of MODY genes are excellent candidate genes for type 2 diabetes. We review recent studies that suggest that common MODY gene variation contributes modestly to the heritability of type 2 diabetes.
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Nejentsev S, Howson JMM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, et al (2007). Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.
Nature,
450(7171), 887-892.
Abstract:
Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group.
Abstract.
Lango H, Ellard S, Colclough K, Frayling TM, Hattersley AT, Weedon MN (2007). Modifying effect of common Type 2 diabetes associated variants on MODY age of onset.
DIABETIC MEDICINE,
24, 11-11.
Author URL.
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JRB, Rayner NW, Freathy RM, et al (2007). Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
Science,
316(5829), 1336-1341.
Abstract:
Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
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De Silva NMG, Steele A, Shields B, Knight B, Parnell K, Weedon MN, Hattersley AT, Frayling TM (2007). The transcription factor 7-like 2 (TCF7L2) gene is associated with Type 2 diabetes in UK community-based cases, but the risk allele frequency is reduced compared with UK cases selected for genetic studies.
Diabet Med,
24(10), 1067-1072.
Abstract:
The transcription factor 7-like 2 (TCF7L2) gene is associated with Type 2 diabetes in UK community-based cases, but the risk allele frequency is reduced compared with UK cases selected for genetic studies.
AIMS: Common polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. METHODS: We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged > or = 45 years (community control subjects). RESULTS: When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13-1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38-1.80), P = 1.4 x 10(-11)] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41-1.54), P < 10(-20)]. CONCLUSION: Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects.
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Freathy RM, Weedon MN, Bennett A, Hypponen E, Relton CL, Knight B, Shields B, Parnell KS, Groves CJ, Ring SM, et al (2007). Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals.
Am J Hum Genet,
80(6), 1150-1161.
Abstract:
Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals.
The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.
Abstract.
Author URL.
Freathy RM, Weedon MN, McCarthy MI, Walker M, Hitman GA, Ring SM, Ben-Shlomo Y, Smith GD, Hattersley AT, Frayling TM, et al (2007). Type 2 diabetes transcription factor 7-like 2 (<i>TCF7L2</i>) risk alleles reduce beta-cell function and increase birth weight.
DIABETIC MEDICINE,
24, 10-10.
Author URL.
Weedon MN, Clark VJ, Qian Y, Ben-Shlomo Y, Timpson N, Ebrahim S, Lawlor DA, Pembrey ME, Ring S, Wilkin TJ, et al (2006). A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.
Am J Hum Genet,
79(6), 991-1001.
Abstract:
A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.
Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal a allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.
Abstract.
Author URL.
Freathy RM, Mitchell SMS, Knight B, Shields B, Weedon MN, Hattersley AT, Frayling TM (2006). A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population.
J Negat Results Biomed,
5Abstract:
A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population.
BACKGROUND: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. RESULTS: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. CONCLUSION: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study.
Abstract.
Author URL.
Ward KJ, Ellard S, Yajnik CS, Frayling TM, Hattersley AT, Venigalla PNS, Chandak GR (2006). Allelic drop-out may occur with a primer binding site polymorphism for the commonly used RFLP assay for the -1131T>C polymorphism of the Apolipoprotein AV gene.
Lipids Health Dis,
5Abstract:
Allelic drop-out may occur with a primer binding site polymorphism for the commonly used RFLP assay for the -1131T>C polymorphism of the Apolipoprotein AV gene.
Apolipoprotein AV (ApoAV) gene variant, -1131T>C, is associated with increased triglyceride concentrations in all ethnic groups studied. An MseI based RFLP analysis is the most commonly used method for genotyping this SNP. We genotyped a large cohort comprising 1185 Asian Indians and 173 UK Caucasians for -1131T>C using an ARMS-PCR based tetra-primer method. For quality control, we re-genotyped approximately 10% random samples from this cohort utilizing the MseI RFLP, which showed a 2.9% (3/102) genotyping error rate between the two methods. To investigate further, we sequenced the 900 bp region around the -1131T>C polymorphism in 25 Asian Indians and 15 UK Caucasians and found a number of polymorphisms including the -987C>T polymorphism. Further analysis of the -987C>T SNP showed a higher rare allele frequency of 0.23 in Asian Indians (n = 158) compared to 0.09 in the UK Caucasians (n = 157). This SNP is located 4 bp from the 3' end of the RFLP forward primer and is in weak linkage disequilibrium with -1131T>C variant (r2 = 0.084 and D' = 1). Repeated RFLP analysis of seven subjects heterozygous for -987C>T (seven times), showed discordant results with the sequence at -1131T>C SNP nearly one third (15/49) of the time. We conclude that presence of -987C>T polymorphism in the forward primer of the MseI RFLP assay may lead to allelic drop-out and generate unforeseen errors in genotyping the -1131T>C polymorphism. Our results also emphasise the need for careful quality control in all molecular genetic studies, particularly while transferring genotyping methods between various ethnic groups.
Abstract.
Author URL.
Porter JR, Rangasami JJ, Ellard S, Gloyn AL, Shields BM, Edwards J, Anderson JM, Shaw NJ, Hattersley AT, Frayling TM, et al (2006). Asian MODY: are we missing an important diagnosis?.
Diabet Med,
23(11), 1257-1260.
Abstract:
Asian MODY: are we missing an important diagnosis?
AIMS: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes where correct diagnosis alters treatment, prognosis and genetic counselling. The first UK survey of childhood MODY identified 20 White, but no Asian children with MODY. We hypothesized that MODY causes diabetes in UK Asians, but is underdiagnosed. METHODS: Children with dominant family histories of diabetes were recruited. Direct sequencing for mutations in the two most common MODY genes; HNF1A (TCF1) and GCK was performed in autoantibody-negative probands. We also compared MODY testing data for Asian and White cases from the Exeter MODY database, to 2001 UK census data. RESULTS: We recruited 30 families and identified three Asian families with MODY gene mutations (two HNF1A, one GCK) and three White UK families (two HNF1A, one GCK). Heterozygous MODY phenotypes were similar in Asians and Whites. Only eight (0.5%) of 1369 UK referrals for MODY testing were known to be Asian, but in 2001 Asians represented 4% of the English/Welsh population and have a higher prevalence of diabetes. CONCLUSIONS: We identified three cases of childhood MODY in UK Asians and demonstrated reduced rates of MODY testing in Asians, which has negative implications for treatment. It is unclear why this is. MODY should be considered in autoantibody-negative Asian diabetes patients lacking evidence of insulin resistance.
Abstract.
Author URL.
Gloyn AL, Mackay DJG, Weedon MN, McCarthy MI, Walker M, Hitman G, Knight BA, Owen KR, Hattersley AT, Frayling TM, et al (2006). Assessment of the role of common genetic variation in the transient neonatal diabetes mellitus (TNDM) region in type 2 diabetes: a comparative genomic and tagging single nucleotide polymorphism approach.
Diabetes,
55(8), 2272-2276.
Abstract:
Assessment of the role of common genetic variation in the transient neonatal diabetes mellitus (TNDM) region in type 2 diabetes: a comparative genomic and tagging single nucleotide polymorphism approach.
Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlapping genes in this region: the transcription factor zinc finger protein associated with cell cycle control and apoptosis (ZAC also known as PLAGL1) and HYMA1, which encodes an untranslated mRNA. Several type 2 diabetes linkage studies have reported linkage to chromosome 6q22-25. We hypothesized that common genetic variation at this TNDM region influences type 2 diabetes susceptibility. In addition to the coding regions, we used comparative genomic analysis to identify conserved noncoding regions, which were resequenced for single nucleotide polymorphism (SNP) discovery in 47 individuals. Twenty-six SNPs were identified. Fifteen tag SNPs (tSNPs) were successfully genotyped in a large case-control (n = 3,594) and family-based (n = 1,654) study. We did not find any evidence of association or overtransmission of any tSNP to affected offspring or of a parent-of-origin effect. Using a study sufficiently powered to detect odds ratios of
Abstract.
Author URL.
Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, et al (2006). Association analysis of 6,736 U.K. subjects provides replication and confirms <i>TCF7L2</i> as a type 2 diabetes susceptibility gene with a substantial effect on individual risk (vol 55, pg 2640, 2006).
DIABETES,
55(12), 3635-3635.
Author URL.
Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, et al (2006). Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.
Diabetes,
55(9), 2640-2644.
Abstract:
Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.
Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10(-11)). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g. rs4506565, 62% transmission, P = 7 x 10(-5)) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is approximately 16%. The overall evidence for association for these variants (P = 4.4 x 10(-14) combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance.
Abstract.
Author URL.
Tsuchiya T, Schwarz PEH, Bosque-Plata LD, Geoffrey Hayes M, Dina C, Froguel P, Wayne Towers G, Fischer S, Temelkova-Kurktschiev T, Rietzsch H, et al (2006). Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.
Mol Genet Metab,
89(1-2), 174-184.
Abstract:
Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.
We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.
Abstract.
Author URL.
Weedon MN, Hattersley AT, Frayling TM (2006). Chapter 1 Transcription factor genes in type 2 diabetes.
Advances in Molecular and Cellular Endocrinology,
5(C), 1-14.
Abstract:
Chapter 1 Transcription factor genes in type 2 diabetes
Researchers in diabetes genetics first became aware of the importance of transcription factor genes in 1996, when two seminal papers described mutations in hepatocyte nuclear factor (HNF)1α and HNF4α as causes of the beta-cell disorder, maturity onset diabetes of the young (MODY). Since then, mutations in the HNF1β, insulin promoter factor (IPF)1 and NeuroD genes, have been described as causes of MODY. Rare mutations in the transcription factor peroxisome proliferative-activated receptor γ (PPARG) have been described as a cause of diabetes associated with severe insulin resistance. Recently researchers have described the importance of common variation in these genes in type 2 diabetes risk. Here, we review the evidence for common variants of transcription factor genes predisposing to type 2 diabetes. We briefly summarise the evidence for the role of the Pro12Ala variant of PPARG in type 2 diabetes and related disorders, as this has been the subject of extensive previous reviews. The evidence that subjects carrying at least one copy of the Ala allele are at reduced risk of type 2 diabetes has now gone beyond the stringent levels of significance required for genetic association studies. of the MODY transcription factor genes that have been extensively analysed, there is strong evidence that variants of HNF1 α and HNF4 α predispose to type 2 diabetes. We conclude that further, comprehensive analyses are needed of all transcription factor genes where rare mutations cause a Mendelian disorder related to type 2 diabetes. © 2006 Elsevier B.V. All rights reserved.
Abstract.
Weedon MN, McCarthy MI, Hitman G, Walker M, Groves CJ, Zeggini E, Rayner NW, Shields B, Owen KR, Hattersley AT, et al (2006). Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.
PLoS Med,
3(10).
Abstract:
Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.
BACKGROUND: a limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. CONCLUSIONS: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.
Abstract.
Author URL.
Patel S, Minton JAL, Weedon MN, Frayling TM, Ricketts C, Hitman GA, McCarthy MI, Hattersley AT, Walker M, Barrett TG, et al (2006). Common variations in the ALMS1 gene do not contribute to susceptibility to type 2 diabetes in a large white UK population.
Diabetologia,
49(6), 1209-1213.
Abstract:
Common variations in the ALMS1 gene do not contribute to susceptibility to type 2 diabetes in a large white UK population.
AIMS/HYPOTHESIS: Alström syndrome is a rare monogenic disorder characterised by retinal dystrophy, deafness and obesity. Patients also have insulin resistance, central obesity and dyslipidaemia, thus showing similarities with type 2 diabetes. Rare mutations in the ALMS1 gene cause severe gene disruption in Alström patients; however, ALMS1 gene polymorphisms are common in the general population. The aim of our study was to determine whether common variants in ALMS1 contribute to susceptibility to type 2 diabetes in the UK population. METHODS: Direct sequencing was performed on coding regions and intron/exon boundaries of the ALMS1 gene in 30 unrelated probands with type 2 diabetes. The linkage disequilibrium (LD; D' and r2) and haplotype structure were examined for the identified variants. The common (minor allele frequency [MAF] >5%) single-nucleotide polymorphisms tagging the common haplotypes (tagged SNPs [tSNPs]) were identified and genotyped in 1985 subjects with type 2 diabetes, 2,047 control subjects and 521 families. RESULTS: We identified 18 variants with MAF between 6 and 38%. Three SNPs efficiently tagged three common haplotypes (rs1881245, rs3820700 and rs1320374). There was no association (all p > 0.05) between the tSNPs and type 2 diabetes in the case-control study and minor alleles of the tSNPs were not overtransmitted to probands with type 2 diabetes in the family study. CONCLUSIONS/INTERPRETATION: Common variations in the ALMS1 gene were not associated with type 2 diabetes in a large study of a white UK population.
Abstract.
Author URL.
Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, Ferrucci L, Paolisso G, Guralnik JM, Frayling TM, et al (2006). Effects of the diabetes linked TCF7L2 polymorphism in a representative older population.
BMC Med,
4Abstract:
Effects of the diabetes linked TCF7L2 polymorphism in a representative older population.
BACKGROUND: a polymorphism in the transcription factor 7-like 2 (TCF7L2) gene has been found to be associated with type 2 diabetes in case-control studies. We aimed to estimate associations of the marker rs7903146 (C/T) polymorphism with fasting glucose, lipids, diabetes prevalence and complications in an older general population. METHODS: in total, 944 subjects aged > or = 65 years from the population representative InCHIANTI study were enrolled in this study. Those with fasting blood glucose of > or = 7 mmol/l or physician diagnosis were considered diabetic. Cut-off points for impaired fasting glucose (IFG) were > or = 5.6 mmol/l to < 7 mmol/l. RESULTS: in the general population sample, minor (T) allele carriers of rs7903146 had higher fasting blood glucose (FBG) (p = 0.028) but lower fasting insulin (p = 0.030) and HOMA2b scores (p = 0.001), suggesting poorer beta-cell function. T allele carriers also had smaller waist circumference (p = 0.009), lower triglyceride levels (p = 0.006), and higher high-density lipoprotein cholesterol (p = 0.008). The prevalence of diabetes or IFG was 32.4% in TT carriers and 23.3% in CC carriers; adjusted OR = 1.67 (95% confidence interval 1.05 to 2.65, p = 0.031). Within the diabetic and IFG groups, fewer T allele carriers had metabolic syndrome features (p = 0.047) or had experienced a myocardial infarction (p = 0.037). Conversely, T allele carriers with diabetes had poorer renal function (reduced 24-hour creatinine clearance, p = 0.013), and possibly more retinopathy (p = 0.067). Physician-diagnosed dementia was more common in the T carriers (in diabetes p = 0.05, with IFG p = 0.024). CONCLUSION: the TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population. Patients with diabetes who are carriers of the minor allele are less likely to have metabolic-syndrome features, but may experience more microvascular complications, although the number of cases was small. If replicated, these findings may have implications for developing treatment approaches tailored by genotype.
Abstract.
Author URL.
Wiltshire S, Bell JT, Groves CJ, Dina C, Hattersley AT, Frayling TM, Walker M, Hitman GA, Vaxillaire M, Farrall M, et al (2006). Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans.
Ann Hum Genet,
70(Pt 6), 726-737.
Abstract:
Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans.
Characterisation of the interactions between susceptibility loci (epistasis) is central to a full understanding of the genetic aetiology and the molecular pathology of complex diseases. We have examined, in British and French pedigrees, evidence for epistasis between the type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 using two complementary linkage-based approaches. Joint two-locus linkage analysis of 1q and 10q in British pedigrees provided significant evidence for interaction (P < or = 0.003) when comparing a general epistasis model with multiplicative or additive-effects-only models. Conditional linkage analysis (which models epistasis as a deviation from multiplicativity only) confirmed these findings, with significant LOD score increases at the 1q (P = 0.0002) and 10q (P = 0.0023) loci. These analyses provided sizeable reductions in the 1-LOD support intervals for both loci. Analyses of the British and French pedigrees together yielded comparable, but not enhanced, findings, with significant (P < or = 0.003) evidence for epistasis in joint two-locus linkage analysis, and during conditional linkage analysis significant increases in linkage evidence at the 1q (P = 0.0002) and 10q (P = 0.0036) loci. Our findings of epistasis nevertheless substantiate the evidence for genuine genetic effects at both loci, facilitate endeavours to fine-map these loci in population samples, and support further examination of this interaction at the nucleotide level by providing a robust prior hypothesis.
Abstract.
Author URL.
Freathy RM, Weedon MN, Shields B, Hitman GA, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2006). Functional variation in VEGF is not associated with type 2 diabetes in a United Kingdom Caucasian population.
JOP,
7(3), 295-302.
Abstract:
Functional variation in VEGF is not associated with type 2 diabetes in a United Kingdom Caucasian population.
CONTEXT: Vascular endothelial growth factor (VEGF) is important for pancreatic beta cell development and function. Common variation in the VEGF gene is associated with altered serum concentrations of VEGF and with several diseases, but its role in type 2 diabetes is not known. The single nucleotide polymorphisms C-2578A (rs699947), G-1154A (rs1570360) and G-634C (rs2010963) in the 5'-region of VEGF are associated with altered serum concentrations of the protein. OBJECTIVE: We performed a large case-control and family-based study to test the hypothesis that these variants are associated with type 2 diabetes in a UK Caucasian population. PARTICIPANTS: We genotyped 1,969 cases, 1,625 controls and 530 families for the three single nucleotide polymorphisms. MAIN OUTCOME MEASURES: Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of alleles to affected offspring. RESULTS: Despite good power (80%) to detect odds ratios of approximately 1.2, there were no significant associations between single alleles or genotypes and type 2 diabetes. Odds ratios (and 95% confidence intervals) comparing case and control allele frequencies for single nucleotide polymorphisms C-2578A, G-1154A and G-634C were 0.97 (0.88-1.07), 0.99 (0.90-1.09) and 0.97 (0.88-1.08), respectively. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in VEGF and type 2 diabetes risk. We have found no evidence that these three single nucleotide polymorphisms, shown previously to alter VEGF concentrations, are risk factors for type 2 diabetes in a large UK Caucasian case-control and family-based study.
Abstract.
Author URL.
Weedon MN, Shields B, Hitman G, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2006). No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians.
Diabetes,
55(11), 3175-3179.
Abstract:
No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians.
Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. There is strong evidence from several previous studies that a common coding variant of ENPP1 (K121Q) and a three-marker haplotype (Q121, IVS20delT-11, and G+1044TGA) are associated with type 2 diabetes and obesity. We examined the impact of ENPP1 variation on type 2 diabetes and obesity in a large U.K. genetic association study. We genotyped the three previously associated polymorphisms in 2,363 type 2 diabetic case and 4,045 control subjects, as well as 1,681 subjects from 529 type 2 diabetic families. We used the same subjects for morbid and moderate obesity association studies. For type 2 diabetes, moderate and morbid obesity, and for both the Q121 and three-marker haplotype, our results exclude with >95% confidence the effect sizes from previous studies (Q121 allele: odds ratio 1.02 [95% CI 0.93-1.12], P = 0.61; 1.00 [0.85-1.18], P = 0.99; and 0.92 [0.70-1.20], P = 0.41; three-marker haplotype: 1.10 [0.96-1.26], P = 0.17; 0.97 [0.77-1.23], P = 0.81; and 0.86 [0.57-1.30], P = 0.46 for type 2 diabetes, moderate, and morbid obesity, respectively). A K121Q type 2 diabetes meta-analysis of all previously published studies remained significant after the inclusion of this study (1.25 [1.10-1.43], P = 0.0007), although there was some evidence of publication bias. In conclusion, we find no evidence that previously associated variants of ENPP1 are associated with type 2 diabetes or obesity in the U.K. population.
Abstract.
Author URL.
Frayling TM, Ward KJ, Weedon MN (2006). Recent Progress in the Identification of Genes Predisposing to the Metabolic Syndrome. , 143-162.
Freathy RM, Weedon MN, Melzer D, Shields B, Hitman GA, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2006). The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.
BMC Med Genet,
7Abstract:
The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.
BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.
Abstract.
Author URL.
Freathy RM, Lonnen KF, Steele AM, Minton JAL, Frayling TM, Hattersley AT, Macleod KM (2006). The impact of the angiotensin-converting enzyme insertion/deletion polymorphism on severe hypoglycemia in Type 2 diabetes.
Rev Diabet Stud,
3(2), 76-81.
Abstract:
The impact of the angiotensin-converting enzyme insertion/deletion polymorphism on severe hypoglycemia in Type 2 diabetes.
The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene (ACE) is associated with altered serum ACE activity. Raised ACE levels and the ACE DD genotype are associated with a 3.2 to 6.8-fold increased risk of severe hypoglycemia in type 1 diabetes. This relationship has not been assessed in type 2 diabetes. We aimed to test for association of the ACE I/D polymorphism with severe hypoglycemia in type 2 diabetes. Patients with type 2 diabetes (n = 308), treated with insulin (n = 124) or sulphonylureas (n = 184), were classified according to whether or not they had previously experienced severe hypoglycemia. Samples of DNA were genotyped for the ACE I/D polymorphism using two alternative polymerase chain reactions to prevent mistyping due to preferential amplification of the D allele. Overall, 12% of patients had previously experienced one or more episodes of severe hypoglycemia. This proportion did not differ between genotype groups (odds ratio (95% confidence limits) for carriers of D allele relative to II homozygotes: 0.79 (0.35-1.78)). This study found no evidence for association of the ACE I/D polymorphism with severe hypoglycemia frequency in patients with type 2 diabetes. However, we cannot rule out a smaller effect (odds ratio
Abstract.
Author URL.
Chandak GR, Ward KJ, Yajnik CS, Pandit AN, Bavdekar A, Joglekar CV, Fall CHD, Mohankrishna P, Wilkin TJ, Metcalf BS, et al (2006). Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans.
BMC Med Genet,
7Abstract:
Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans.
BACKGROUND: the APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects. METHODS: We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants. RESULTS: the APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent (3% vs. 6% p = 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07). CONCLUSION: This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The -1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease.
Abstract.
Author URL.
Weedon MN, Owen KR, Shields B, Hitman G, Walker M, McCarthy MI, Hattersley AT, Frayling TM (2005). A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population.
Diabetes,
54(8), 2487-2491.
Abstract:
A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population.
HNF1alpha (TCF1) is a key transcription factor that is essential for pancreatic beta-cell development and function. Rare mutations of HNF1alpha cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1alpha variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1alpha gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid-changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) >1.25 for all tSNPs. The rare V98 allele (approximately 3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99-1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08-1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (
Abstract.
Author URL.
Zeggini E, Parkinson JRC, Halford S, Owen KR, Walker M, Hitman GA, Levy JC, Sampson MJ, Frayling TM, Hattersley AT, et al (2005). Examining the relationships between the Pro12Ala variant in PPARG and Type 2 diabetes-related traits in UK samples.
Diabet Med,
22(12), 1696-1700.
Abstract:
Examining the relationships between the Pro12Ala variant in PPARG and Type 2 diabetes-related traits in UK samples.
AIMS: the Pro12Ala polymorphism in the PPARG gene alters amino acid sequence and has shown consistent association with susceptibility to Type 2 diabetes in several populations. The present study makes use of large, well-characterized case-control resources to enhance understanding of this susceptibility effect by examining related traits, such as body mass index (BMI), waist-hip ratio and age at diagnosis. METHODS: the Pro12Ala variant was genotyped in two UK case samples, ascertained for positive family history and/or early onset of Type 2 diabetes (combined n=971); and in 1257 ethnically matched control subjects. RESULTS: There were significant associations of the Pro12Ala single nucleotide polymorphism (SNP) genotypes with diabetes in both case-control comparisons (P=0.025 and P=0.039). Comparing individuals homozygous for the Pro allele, with those carrying an Ala allele, the combined odds ratio for diabetes was 1.40 (95% CIs, 1.12-1.76, P=0.0031). There was no association between the variant and either waist-hip ratio or age at diagnosis. Proline homozygosity was associated with increased BMI in one patient group (P=0.013) and decreased BMI in the other (P=0.038). CONCLUSIONS: This study confirms that variation within PPARG influences susceptibility to Type 2 diabetes in UK samples. However, the relationship between PPARG variation and BMI is more complex, and studies in much larger sample sets will be required to more precisely characterize the effect of this variant on adiposity.
Abstract.
Author URL.
Weedon MN, Frayling TM, Shields B, Knight B, Turner T, Metcalf BS, Voss L, Wilkin TJ, McCarthy A, Ben-Shlomo Y, et al (2005). Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.
Diabetes,
54(2), 576-581.
Abstract:
Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.
Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK beta-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the a allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The a allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the a allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an a allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight.
Abstract.
Author URL.
Zeggini E, Groves CJ, Parkinson JRC, Halford S, Owen KR, Frayling TM, Walker M, Hitman GA, Levy JC, O'Rahilly S, et al (2005). Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.
Diabetologia,
48(10), 2013-2017.
Abstract:
Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.
AIMS/HYPOTHESIS: the proinflammatory cytokine TNF-alpha has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-alpha (TNF) has shown inconsistent associations with susceptibility to both conditions. Additionally, the coding non-synonymous variant T60N in the neighbouring LTA gene has been reported to be associated with type 2 diabetes. The present study aimed to obtain a robust assessment of the role of variation in the tightly linked TNF/LTA region in diabetes susceptibility by genotyping TNF and LTA variants in large case-control resources. MATERIALS AND METHODS: the G-308A and G-238A TNF promoter variants and the LTA T60N polymorphism were genotyped in two UK case samples that were ascertained for positive family history and/or early onset of type 2 diabetes (combined n=858) and in 1,257 ethnically matched controls. RESULTS: There were no significant associations between the T60N, G-308A or G-238A genotype and type 2 diabetes in the combined analysis (exact Cochran-Mantel-Haenszel statistic for ordered genotypes for T60N, p=0.69; for G-308A, p=0.51; for G-238A, p=0.16). CONCLUSIONS/INTERPRETATION: the present study, one of the largest association analyses yet reported at this locus, provides no evidence that the specific TNF or LTA variants examined influence susceptibility to type 2 diabetes. More comprehensive studies of the TNF/LTA locus in substantially larger sample sets are required to establish whether genome sequence variation at this locus truly influences susceptibility to type 2 diabetes.
Abstract.
Author URL.
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JMCL, Molnes J, et al (2004). Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
N Engl J Med,
350(18), 1838-1849.
Abstract:
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.
Abstract.
Author URL.
Liew CF, Groves CJ, Wiltshire S, Zeggini E, Frayling TM, Owen KR, Walker M, Hitman GA, Levy JC, O'rahilly S, et al (2004). Analysis of the contribution to type 2 diabetes susceptibility of sequence variation in the gene encoding stearoyl-CoA desaturase, a key regulator of lipid and carbohydrate metabolism.
Diabetologia,
47(12), 2168-2175.
Abstract:
Analysis of the contribution to type 2 diabetes susceptibility of sequence variation in the gene encoding stearoyl-CoA desaturase, a key regulator of lipid and carbohydrate metabolism.
AIMS/HYPOTHESIS: Stearoyl-CoA desaturase (SCD) is emerging as a key regulator of lipid and carbohydrate metabolism. Scd-null mice display a beneficial metabolic phenotype characterised by resistance to obesity, diabetes and hyperlipidaemia. The human homologue, SCD, maps to a region of chromosome 10 linked to type 2 diabetes, and SCD activity correlates with insulin sensitivity. Given this strong positional and biological candidacy, the present study sought to establish whether sequence variation in SCD influences susceptibility to type 2 diabetes and related traits. METHODS: the SCD gene was resequenced in 23 diabetic subjects. Six variants within coding and adjacent sequence, including a non-synonymous SNP in exon 5 (M224L), were selected for genotyping in a primary set of 608 diabetic subjects and 600 control subjects. RESULTS: There was no association (at the allele, genotype or haplotype level) with type 2 diabetes, although genotype frequencies at the +14301 A>C SNP in the 3' untranslated region showed borderline association (p~0.06) when evidence for linkage was taken into account. However, replication studies (350 young-onset diabetic patients; 747 controls) failed to confirm any relationship with diabetes for this variant. No significant associations were seen for diabetes-related traits including BMI and waist-to-hip ratio. CONCLUSIONS/INTERPRETATION: the present study, the first reported analysis of this gene, indicates that the SCD variants typed do not explain chromosome-10-encoded susceptibility to type 2 diabetes. Although this study provided no evidence that SCD sequence variation influences diabetes susceptibility or related traits, SCD remains a major target for pharmaceutical and/or environmental manipulation.
Abstract.
Author URL.
Zeggini E, Parkinson J, Halford S, Owen KR, Frayling TM, Walker M, Hitman GA, Levy JC, Sampson MJ, Feskens EJM, et al (2004). Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset.
Diabetes,
53(12), 3319-3322.
Abstract:
Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset.
The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86-1.44, P = 0.44]) an updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02-1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect.
Abstract.
Author URL.
Weedon MN, Owen KR, Shields B, Hitman G, Walker M, McCarthy MI, Love-Gregory LD, Permutt MA, Hattersley AT, Frayling TM, et al (2004). Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population.
Diabetes,
53(11), 3002-3006.
Abstract:
Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population.
Hepatocyte nuclear factor (HNF)-4alpha is part of a transcription factor network that is key for the development and function of the beta-cell. Rare mutations in the HNF4alpha gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4alpha gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.
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Author URL.
Wiltshire S, Frayling TM, Groves CJ, Levy JC, Hitman GA, Sampson M, Walker M, Menzel S, Hattersley AT, Cardon LR, et al (2004). Evidence from a large U.K. family collection that genes influencing age of onset of type 2 diabetes map to chromosome 12p and to the MODY3/NIDDM2 locus on 12q24.
Diabetes,
53(3), 855-860.
Abstract:
Evidence from a large U.K. family collection that genes influencing age of onset of type 2 diabetes map to chromosome 12p and to the MODY3/NIDDM2 locus on 12q24.
Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes.
Abstract.
Author URL.
Mitchell SMS, Hattersley AT, Knight B, Turner T, Metcalf BS, Voss LD, Davies D, McCarthy A, Wilkin TJ, Smith GD, et al (2004). Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations.
J Clin Endocrinol Metab,
89(1), 310-317.
Abstract:
Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations.
The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with beta-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.
Abstract.
Author URL.
Owen KR, Evans JC, Frayling TM, Hattersley AT, McCarthy MI, Walker M, Hitman GA (2004). Role of the D76N polymorphism of insulin promoter factor-1 in predisposing to Type 2 diabetes.
Diabetologia,
47(5), 957-958.
Author URL.
Weedon MN, Hattersley AT, Frayling TM (2004). Tall stories: the fundamental difficulties of genetic association studies.
Clin Endocrinol (Oxf),
60(1), 145-146.
Author URL.
Frayling TM, Lindgren CM, Chevre JC, Menzel S, Wishart M, Benmezroua Y, Brown A, Evans JC, Rao PS, Dina C, et al (2003). A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.
Diabetes,
52(3), 872-881.
Abstract:
A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.
Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.
Abstract.
Author URL.
Groves CJ, Wiltshire S, Smedley D, Owen KR, Frayling TM, Walker M, Hitman GA, Levy JC, O'Rahilly S, Menzel S, et al (2003). Association and haplotype analysis of the insulin-degrading enzyme (IDE) gene, a strong positional and biological candidate for type 2 diabetes susceptibility.
Diabetes,
52(5), 1300-1305.
Abstract:
Association and haplotype analysis of the insulin-degrading enzyme (IDE) gene, a strong positional and biological candidate for type 2 diabetes susceptibility.
The gene for insulin-degrading enzyme (IDE) represents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several populations; the rat homolog has been directly implicated in diabetes susceptibility; and known functions of IDE support an important role in glucose homeostasis. We sought evidence for association between IDE variation and diabetes by mutation screening, defining local haplotype structure, and genotyping variants delineating common haplotypic diversity. An initial case-control analysis (628 diabetic probands from multiplex sibships and 604 control subjects) found no haplotypic associations, although one variant (IDE2, -179T-->C) showed modest association with diabetes (odds ratio [OR]1.25, P = 0.03). Linkage partitioning analyses failed to support this association, but provided borderline evidence for a different variant (IDE10, IVS20-405A-->G) (P = 0.06). Neither variant was associated with diabetes when replication was sought in 377 early onset diabetic subjects and 825 control subjects, though combined analysis of all typed cohorts indicated a nominally significant effect at IDE2 (OR 1.21 [1.04-1.40], P = 0.013). In the absence of convincing support for this association from linkage partitioning or analyses of continuous measures of glycemia, we conclude that analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans.
Abstract.
Author URL.
Lockwood CR, Frayling TM (2003). Combining genome and mouse knockout expression data to highlight binding sites for the transcription factor HNF1alpha.
In Silico Biol,
3(1-2), 57-70.
Abstract:
Combining genome and mouse knockout expression data to highlight binding sites for the transcription factor HNF1alpha.
The identification of regulatory elements in silico is an important method for inferring function from sequence data, but it is uncertain which methods are best. We used a novel combination of expression data from a TCF1 knockout mouse (TCF1 codes for the transcription factor HNF1a), and human and mouse genome sequences, to search 2kb upstream of 28 genes downregulated in TCF1 null mice compared to wild type mice. We wrote software (http://www.BindGene.org) to search for and assign p-values to potential binding sites. This identified 8 genes as candidates for being directly regulated by HNF1a: LIPC, CRP, F13B, PRODH2, HSD17B2, SCL7A9, SLC16A7, PAH. There was evidence for conservation between human and mouse for all these regions identified as containing putative binding sites. For three of the genes identified there was experimental evidence for an HNF1a binding site. For comparison we also examined 25 genes up-regulated in TCF1 null mice; only one gene was selected and there was little evidence for conservation of this putative binding site between human and mouse. This result was consistent with HNF1a being a gene transcription activator. Another 6 up-regulated genes had unexpectedly high p-values, suggesting that possibly HNF1a sites have been suppressed from these genes. In conclusion, gene expression data from transgenic animals lacking a transcription factor can be used to identify DNA binding sites for that factor.
Abstract.
Author URL.
Ward KJ, Shields B, Knight B, Salzmann MB, Hattersley AT, Frayling TM (2003). Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy.
Lipids Health Dis,
2Abstract:
Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy.
BACKGROUND: Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those in the Apolipoprotein E (ApoE), Lipoprotein Lipase (LPL), and most recently, the Apolipoprotein AV (ApoAV) gene. However, less is known about how variants in these genes alter triglyceride concentrations in pregnancy or affect fetal growth. We aimed to determine the effect of the recently identified ApoAV gene on triglycerides in pregnancy and fetal growth. We assessed the role of two ApoAV haplotypes, defined by the C and W alleles of the -1131T>C and S19W polymorphisms, in 483 pregnant women and their offspring from the Exeter Family Study of Childhood Health. RESULTS: the -1131T>C and S19W variants have rare allele frequencies of 6.7% and 4.9% and are present in 13.4% and 9.7% of subjects respectively. In carriers of the -1131C and 19W alleles triglyceride concentrations were raised by 11.0% (1.98 mmol/ l(1.92 - 2.04) to 2.20 mmol/l (2.01 - 2.42), p = 0.035; and 16.2% (1.97 mmol/l (1.91 - 2.03) to 2.29 mmol/l (2.12 - 2.48), p < 0.001 respectively. There is nominally significant evidence that the -1131T>C variant is having an effect on maternal height (164.9 cm (164.3 - 165.5) to 167.0 cm (165.2 - 168.8), p = 0.029). There was no evidence that ApoAV genotype alters any other anthropometric measurements or biochemistries such as High Density Lipoprotein Cholesterol (HDL-C) or Low Density Lipoprotein Cholesterol (LDL-C). There is nominally significant evidence that the presence of a maternal -1131C variant alters fetal birth length (50.2 cm (50.0 - 50.4) to 50.9 cm (50.3 - 51.4), p = 0.022), and fetal birth crown-rump length (34.0 cm (33.8 - 34.1) to 34.5 cm (34.1 - 35.0), p = 0.023). There is no evidence that ApoAV genotype alters fetal birth weight or other fetal growth measurements. CONCLUSION: in conclusion variation in the ApoAV gene raises triglyceride concentrations in pregnancy, as well as normolipaemic states and there is preliminary evidence that it alters fetal growth parameters.
Abstract.
Author URL.
Mitchell SMS, Weedon MN, Owen KR, Shields B, Wilkins-Wall B, Walker M, McCarthy MI, Frayling TM, Hattersley AT (2003). Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects.
Diabetes,
52(5), 1276-1279.
Abstract:
Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects.
The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a. Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The a allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects (n = 348), their parents (n = 272), or young nondiabetic adults (n = 925). However, the rare (
Abstract.
Author URL.
Lockwood CR, Bingham C, Frayling TM (2003). In silico searching of human and mouse genome data identifies known and unknown HNF1 binding sites upstream of beta-cell genes.
Mol Genet Metab,
78(2), 145-151.
Abstract:
In silico searching of human and mouse genome data identifies known and unknown HNF1 binding sites upstream of beta-cell genes.
HNF1-alpha is a transcription factor present in beta-cells. Mutations in the HNF1-alpha gene cause maturity-onset diabetes of the young (MODY), but the exact mechanism is not known. Several studies have highlighted genes down-regulated in beta-cells lacking this gene, but it is not clear if these are directly regulated by HNF1-alpha. To better understand this, we used human and mouse genome data to examine 29 genes expressed in the beta-cell. Using an in silico approach (with software available at www.BindGene.org) we examined 2kb upstream of each gene for possible HNF1 binding sequences. In five genes we also examined 100kb upstream of each gene, but only the portions strongly conserved between humans and mice. We identified nine putative HNF1 binding sites upstream of seven genes (p
Abstract.
Author URL.
TFrayling, Gloyn AL, Knight BA, Weedon MN (2003). Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic beta-Cell K(ATP) Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with Type 2 diabetes. Diabetes, 52(2), 568-572.
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, et al (2003). Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.
Diabetes,
52(2), 568-572.
Abstract:
Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.
The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.
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Author URL.
Weedon MN, Schwarz PEH, Horikawa Y, Iwasaki N, Illig T, Holle R, Rathmann W, Selisko T, Schulze J, Owen KR, et al (2003). Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility.
Am J Hum Genet,
73(5), 1208-1212.
Author URL.
Weedon MN, Gloyn AL, Frayling TM, Hattersley AT, Davey Smith G, Ben-Shlomo Y (2003). Quantitative traits associated with the Type 2 diabetes susceptibility allele in Kir6.2.
Diabetologia,
46(7), 1021-1023.
Author URL.
Weedon MN, Turner M, Knight B, Clark P, Hattersley AT, Frayling TM (2003). Variants in the aromatase gene and on the Y-chromosome are not associated with adult height or insulin resistance in a UK population.
Clin Endocrinol (Oxf),
59(2), 175-179.
Abstract:
Variants in the aromatase gene and on the Y-chromosome are not associated with adult height or insulin resistance in a UK population.
OBJECTIVE: to assess the association of polymorphisms in the aromatase gene (CYP19) and on the Y-chromosome, with adult height and insulin resistance in a UK Caucasian population, after a recent report indicated these variants explain 4 cm of adult male height variation. PATIENTS AND DESIGN: We performed an association study using 917 healthy UK Caucasian subjects from the Exeter Family Study, an ongoing consecutive-birth cohort. Our study had > 85% (95% for the CYP19 variant; 85% for the Y variant) power to detect the association suggested by the previous study. MEASUREMENTS: Subjects'CYP19 genotype were determined using tetra-primer PCR, and the Y-chromosome variant genotype was identified using a restriction fragment length polymorphism (RFLP) method. Trained research nurses were responsible for measurement of height. Fasting insulin concentration was determined by an immunoenzymometric assay. RESULTS: We did not find any evidence for an effect of the CYP19 polymorphism or Y-RFLP on adult height (P > 0.83 for both variants). In addition, there was no evidence for an effect on insulin resistance in a subset of 416 subjects (P > 0.46). CONCLUSION: We have not confirmed the initial observation in a larger replication cohort. Our results highlight the importance of replicating initial results from genetic association studies.
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Author URL.
Frayling TM, Wiltshire S, Hitman GA, Walker M, Levy JC, Sampson M, Groves CJ, Menzel S, McCarthy MI, Hattersley AT, et al (2003). Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11.
Diabetes,
52(7), 1857-1863.
Abstract:
Young-onset type 2 diabetes families are the major contributors to genetic loci in the Diabetes UK Warren 2 genome scan and identify putative novel loci on chromosomes 8q21, 21q22, and 22q11.
A young onset of type 2 diabetes is likely to result, in part, from greater genetic susceptibility. Young-onset families may therefore represent a group in which genes are more easily detectable by linkage. To test this hypothesis, we conducted age at diagnosis (AAD) stratified linkage analyses in the Diabetes UK Warren 2 sibpairs. In the previously published unstratified analysis, evidence for linkage (logarithm of odds [LOD] >1.18) was found at seven loci. The LOD scores at these seven loci were higher in the 245 families with AAD 55 years (G55). Five of these seven loci (1q24-25, 5q13, 8p21-22, 8q24.2, and 10q23.2) had LOD scores >1.18 in the L55 subset but only one (8p21-22) did in the G55 subset. Two additional loci (8q21.13 and 21q22.2) showed evidence for linkage in the L55 subset alone. Another locus (22q11) showed evidence for linkage in a subset of families with AAD
Abstract.
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Andersen G, Hansen T, Gharani N, Frayling TM, Owen KR, Sampson M, Ellard S, Walker M, Hitman GA, Hattersley AT, et al (2002). A common Gly482Ser polymorphism of <i>PGC-1</i> is associated with type 2 diabetes mellitus in two European populations.
DIABETES,
51, A49-A50.
Author URL.
Frayling TM, Hattersley AT, McCarthy A, Holly J, Mitchell SMS, Gloyn AL, Owen K, Davies D, Smith GD, Ben-Shlomo Y, et al (2002). A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations.
Diabetes,
51(7), 2313-2316.
Abstract:
A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations.
IGF-I has a critical role in growth and metabolism. A microsatellite polymorphism 1 kb upstream to the IGF-I gene has recently been associated with several adult phenotypes. In a large Dutch cohort, the absence of the commonest allele (Z) was associated with reduced serum IGF-I levels, reduced height, and an increased risk of type 2 diabetes and myocardial infarction. This result has not been replicated, and the role of this polymorphism in these traits in U.K. subjects is not known. We sought further evidence for the involvement of this variant in type 2 diabetes using a case-control study and IGF-I and diabetes-related traits in a population cohort of 640 U.K. individuals aged 25 years. Absence of the common allele was not associated with type 2 diabetes (odds ratio 0.70, 95% CI 0.47-1.04 for X/X versus Z/Z genotype, chi(2) test for trend across genotypes, P = 0.018). In the population cohort, the common allele (Z) was associated with decreased IGF-I levels (P = 0.01), contrary to the Dutch study, but not with adult height (P = 0.23), glucose tolerance (P = 0.84), oral glucose tolerance test-derived values of beta-cell function (P = 0.90), or insulin resistance (P = 0.66). There was no association with measures of fetal growth, including birth weight (P = 0.17). Our results do not support the previous associations and suggest that the promoter microsatellite is unlikely to be functionally important.
Abstract.
Author URL.
Frayling TM, Minton J, Knight B, Turner T, Barrett TG, Hattersley AT (2002). A putative type 2 diabetes susceptibility allele in the <i>WFS1</i> gene and fetal growth.
DIABETES,
51, A264-A264.
Author URL.
Shore AC, Evans JC, Frayling TM, Clark PM, Lee BC, Horikawa Y, Hattersley AT, Tooke JE (2002). Association of calpain-10 gene with microvascular function.
Diabetologia,
45(6), 899-904.
Abstract:
Association of calpain-10 gene with microvascular function.
AIMS/HYPOTHESIS: Genotype could influence vascular function. In some populations, Calpain 10 gene polymorphisms increase susceptibility to diabetes or insulin resistance. Alterations in microvascular function could contribute to insulin resistance. This study investigated whether polymorphisms in the Calpain-10 gene influence microvascular function. METHODS: Skin maximum microvascular hyperaemia to local heating on the dorsum of the foot (30 min at 43 degrees C) was measured by Laser Doppler Fluximetry in 37 healthy volunteers. All were normoglycaemic according to World Health Organisation criteria, normotensive and not on any medication. Four polymorphisms in the calpain-10 gene were typed: SNP-44, SNP-43, SNP-19, SNP-63. The SNP common to all the described high risk haplotypes is the G-allele at SNP-43. This intron 3 polymorphism appears to influence gene expression. Microvascular function was examined in relation to polymorphisms at this site alone as well as the effects of the known extended high risk haplotypes using the SNP's above. RESULTS: Maximum microvascular hyperaemia was increased in the 21 subjects with G/G genotypes at SNP-43 compared to the combined group of subjects ( G/ a genotype at SNP-43 ( n=12) + A/ a genotype at SNP-43 ( n=4)), and the minimum microvascular resistance was reduced 49.4 (39.6-94.2) vs 67.5 (39.1-107.3) mmHg/V, p=0.007). Haplotype analysis of the hyperaemic response revealed no significant differences between haplotypes. The two groups did not differ in terms of anthropometric measures, blood pressure, insulin resistance or glucose. CONCLUSIONS/INTERPRETATION: the polymorphism that confers susceptibility to Type II (non-insulin-dependent) diabetes mellitus in some populations is associated in United Kingdom Caucasians with enhanced microvascular function in the presence of normoglycaemia.
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Author URL.
Minton JAL, Hattersley AT, Owen K, McCarthy MI, Walker M, Latif F, Barrett T, Frayling TM (2002). Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations.
Diabetes,
51(4), 1287-1290.
Abstract:
Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations.
Mutations in the WFS1 gene cause beta-cell death, resulting in a monogenic form of diabetes known as Wolfram syndrome. The role of variation in WFS1 in type 2 diabetes susceptibility is not known. We sequenced the WFS1 gene in 29 type 2 diabetic probands and identified 12 coding variants. We used 152 parent-offspring trios to look for familial association; the R allele at residue 456 (P = 0.04) and the H allele at residue 611 (P = 0.05) as well as the R456-H611 haplotype (P = 0.032) were overtransmitted to affected offspring from heterozygous parents. In a further cohort of 327 type 2 diabetic subjects and 357 normoglycemic control subjects, the H611 allele and the R456-H611 haplotype were present in more type 2 diabetic subjects than control subjects (one-tailed P = 0.06 and P = 0.023, respectively). In a combined analysis, the H611 allele was present in 60% of all diabetes chromosomes and 55% of all control chromosomes (odds ratio [OR] 1.24 [95% CI 1.03-1.48], P = 0.02), and the R456-H611 haplotype was significantly more frequent in type 2 diabetic subjects than in control subjects (60 vs. 54%, OR 1.29 [95% CI 1.08-1.54], P = 0.0053). Our results provide the first evidence that variation in the WFS1 gene may influence susceptibility to type 2 diabetes.
Abstract.
Author URL.
Frayling TM, Hattersley AT, Smith GD, Ben-Shlomo Y (2002). Conflicting results on variation in the IGFI gene highlight methodological considerations in the design of genetic association studies.
Diabetologia,
45(11), 1605-1606.
Author URL.
Wiltshire S, Frayling TM, Hattersley AT, Hitman GA, Walker M, Levy JC, O'Rahilly S, Groves CJ, Menzel S, Cardon LR, et al (2002). Evidence for linkage of stature to chromosome 3p26 in a large U.K. Family data set ascertained for type 2 diabetes.
Am J Hum Genet,
70(2), 543-546.
Abstract:
Evidence for linkage of stature to chromosome 3p26 in a large U.K. Family data set ascertained for type 2 diabetes.
We have analyzed data from 573 pedigrees from the United Kingdom for evidence for linkage to loci influencing adult stature. Our data set comprised 1,214 diabetic and 163 nondiabetic siblings for whom height data were available. We used variance-components analysis implemented in GENEHUNTER 2 and a modification of the Haseman-Elston regression method, HE-COM. We found evidence for a locus on 3p26 (LOD score 3.17) influencing height in this adult sample, with less-significant evidence for loci on chromosomes 7, 10, 15, 17, 19, and 20. Our findings extend similar recent studies in Scandinavian and Quebecois populations, adding further evidence that height is indeed under the control of multiple genes.
Abstract.
Author URL.
Minton JAL, Hattersley AT, Owen K, Mccarthy MI, Walker M, Latif F, Barrett TG, Frayling TM (2002). Genetic variation in the WFS1 gene: Association and linkage studies in type 2 diabetes UK Populations.
DIABETES,
51, A39-A39.
Author URL.
Gloyn AL, Desai M, Clark A, Levy JC, Holman RR, Frayling TM, Hattersley AT, Ashcroft SJH (2002). Human calcium/calmodulin-dependent protein kinase II gamma gene (CAMK2G): cloning, genomic structure and detection of variants in subjects with type II diabetes.
Diabetologia,
45(4), 580-583.
Abstract:
Human calcium/calmodulin-dependent protein kinase II gamma gene (CAMK2G): cloning, genomic structure and detection of variants in subjects with type II diabetes.
AIMS/HYPOTHESIS: Ca(2+)/calmodulin-dependent protein kinase II, is expressed in the pancreatic beta cells and is activated by glucose and other secretagogues in a manner correlating with insulin secretion. The activation of Ca(2+)/calmodulin-dependent protein kinase II mediates some of the actions of Ca(2+) on the exocytosis of insulin. We therefore investigated the gene encoding the gamma isoform ( CAMK2G) which has been shown to be expressed in human beta cells as a candidate gene for Type II (non-insulin-dependent) diabetes mellitus. METHODS: Human CAMK2G was cloned from a total human P1 artificial chromosome library using a partial Ca(2+)/calmodulin-dependent protein kinase gamma(E) cDNA probe. Positive PAC clones were localised to chromosome 10q22 by fluorescence in situ hybridisation. To obtain structural information and the sequences of the exon-intron boundaries, the published genomic structures of the rat and mouse genes allowed the putative exon-intron boundaries of human CAMK2G to be amplified by vectorette polymerase chain reaction and sequenced. Sequence variants in each exon were identified using single stranded conformational polymorphism analysis. RESULTS: the human CAMK2G gene comprises 22 exons which range in size between 43 to 230 bp. Screening of the exons and exon-intron boundaries identified two single nucleotide polymorphisms. These did not show association with diabetes in 122 patients and 144 control subjects. CONCLUSIONS/INTERPRETATION: We have identified the genomic structure of CAMK2G to enable further study of this potential candidate gene. Variation in this gene is not strongly associated with diabetes in Caucasians in the United Kingdom. We have identified two single nucleotide polymorphisms which, with appropriately large case control studies, can be used to assess the role of CAMK2G in the susceptibility to Type II diabetes.
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Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT (2002). Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers.
Diabetes Care,
25(12), 2287-2291.
Abstract:
Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers.
OBJECTIVE: in animals, experimentally induced maternal hyperglycemia during pregnancy results in hyperglycemic offspring. Similarly, Pima Indian offspring with mothers who are diabetic at the time of pregnancy have increased risk of early-onset diabetes. We hypothesized that exposure to hyperglycemia in utero would decrease the age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY) due to a mutation in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene. RESEARCH DESIGN AND METHODS: We analyzed the affect of maternal diabetes on age at diagnosis of diabetes in 150 HNF-1alpha gene mutation carriers from 55 families. RESULTS: Age at diagnosis in HNF-1alpha mutation carriers was younger when the mother was diagnosed before pregnancy compared with when the mother was diagnosed after pregnancy (15.5 +/- 5.4 vs. 27.5 +/- 13.1 years, P < 0.0001). This is unlikely to represent a generalized familial decrease in age at diagnosis due to a more severe mutation, because no difference was seen in age of the offspring at diagnosis of diabetes when the father was diagnosed at a young age, and a similar trend was seen when only the single common mutation, P291fsinsC, was analyzed. CONCLUSIONS: We conclude that maternal hyperglycemia during pregnancy probably increases the penetrance of HNF-1alpha mutations. The potential role of exposure to hyperglycemia in utero in a monogenic diabetic subgroup warrants prospective study.
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Author URL.
Mitchell SMS, Hattersley AT, McCarthy A, Turner T, Knight B, Davies D, Smith GD, Ben-Shlomo Y, Frayling TM (2002). No evidence for role of <i>INS-VNTR</i> locus in determining birthweight.
DIABETES,
51, A261-A261.
Author URL.
Mitchell SMS, Vaxillaire M, Thomas H, Parrizas M, Benmezroua Y, Costa A, Hansen T, Owen KR, Tuomi T, Pirie F, et al (2002). Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.
Diabetologia,
45(9), 1344-1348.
Abstract:
Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.
AIMS/HYPOTHESIS: the recently identified alternative promoter (P2) of HNF-4 alpha is the major HNF-4 alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility. METHODS: to assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha. RESULTS: Two variants were found that were not present in the control subjects. The -79 C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276 G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79 C/T or -276 G/T single nucleotide substitutions. CONCLUSION/INTERPRETATION: We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4 alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.
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Author URL.
Mitchell SMS, Gloyn AL, Owen KR, Hattersley AT, Frayling TM (2002). The role of the HNF4alpha enhancer in type 2 diabetes.
Mol Genet Metab,
76(2), 148-151.
Abstract:
The role of the HNF4alpha enhancer in type 2 diabetes.
The genetic causes of type 2 diabetes are not well understood. The disease has been linked to chromosome 20q12-q13.1 a region which harbors the transcription factor HNF4alpha. Mutations in the coding region of HNF4alpha cause maturity onset diabetes of the young, an autosomal dominant form of diabetes, but do not account for the linkage to this region. An enhancer element has recently been characterized 6 kb 5' of the HNF4alpha P1 promoter containing binding sites for the transcription factors HNF1, HNF4, HNF3, and C/EBP, which are overlapped by glucocorticoid consensus sites. We hypothesized that variation in the enhancer element disrupts HNF4alpha expression in the liver and increases susceptibility to type 2 diabetes. We screened for variants of the enhancer element in 39 white UK young onset diabetic subjects, giving >95% power to identify variants with minor allele frequencies of >5%. No variants of the enhancer element were found in this population. We conclude that variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes.
Abstract.
Author URL.
Mitchell SMS, Frayling TM (2002). The role of transcription factors in maturity-onset diabetes of the young.
Mol Genet Metab,
77(1-2), 35-43.
Abstract:
The role of transcription factors in maturity-onset diabetes of the young.
The study of maturity-onset diabetes of the young (MODY), an autosomal dominant form of early-onset diabetes mellitus characterised by defective insulin secretion has been extremely successful in two ways. Firstly it has enabled definitive diagnosis for patients. This allows more accurate prediction of disease and treatment requirements. Secondly it has facilitated an increased understanding of the genes and pathways that are crucial for normal beta-cell function. Five of the six MODY genes, TCF1 (encoding HNF-1alpha), TCF2 (encoding HNF-1beta) HNF4A, insulin promoter factor (IPF)1, and NEUROD1, are transcription factors that operate in a complex network of gene regulation. Several genes have been shown to be regulated by the MODY transcription factors in a beta-cell specific manner. This includes the co-regulation of HNF-1alpha and HNF-4alpha by each other. The exact mechanism of how mutations in these transcription factors result in diabetes in humans remains unknown. However, current opinion favours pleiotropic adverse effects on many genes; extensive in vitro and in vivo studies of these genes has highlighted their importance in both glucose sensing-insulin secretion coupling and maintaining the fully differentiated beta-cell phenotype.
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Author URL.
Mccarthy MI, Wiltshire S, Hattersley AT, Walker M, Hitman GA, O'Rahilly S, Levy JC, Menzel S, Frayling TM, Groves CJ, et al (2002). The type 2 diabetes susceptibility region on chromosome 1q: Studies in UK and French nuclear families.
DIABETES,
51, A50-A51.
Author URL.
Lynn S, Evans JC, White C, Frayling TM, Hattersley AT, Turnbull DM, Horikawa Y, Cox NJ, Bell GI, Walker M, et al (2002). Variation in the calpain-10 gene affects blood glucose levels in the British population.
Diabetes,
51(1), 247-250.
Abstract:
Variation in the calpain-10 gene affects blood glucose levels in the British population.
Variation in the calpain-10 gene (CAPN10) has been shown to be associated with type 2 diabetes in Mexican-Americans and in at least three Northern European populations. Studies in nondiabetic Pima Indians showed that one of the at-risk DNA polymorphisms, single-nucleotide polymorphism (SNP)-43, in CAPN10 was associated with insulin resistance, and individuals with the G/G-genotype had significantly higher fasting plasma glucose and 2-h insulin concentrations after a 75-g oral glucose tolerance test (OGTT). We have examined the effect of variation in CAPN10 on plasma glucose and insulin levels in a group of 285 nondiabetic British subjects after a 75-g OGTT. The results showed that subjects with G/G genotype at SNP-43 had higher 2-h plasma glucose levels than the combined G/A + A/A group (P = 0.05). We also examined the SNP-43, -19, and -63 haplotype combination 112/121, which is associated with an approximately threefold increased risk of diabetes. Subjects with the 112/121 haplotype combination (n = 29) had increased fasting (P = 0.004) and 2-h plasma glucose levels (P = 0.003) compared with the rest of the study population after correction for age, sex, and BMI. The 112/121 haplotype combination was also associated with a marked decrease in the insulin secretory response, adjusted for the level of insulin resistance (P = 0.002). We conclude that genetic variation in the CAPN10 gene influences blood glucose levels in nondiabetic British subjects and that this is due, at least in part, to the effects of calpain-10 on the early insulin secretory response.
Abstract.
Author URL.
Haddad L, Evans JC, Gharani N, Robertson C, Rush K, Wiltshire S, Frayling TM, Wilkin TJ, Demaine A, Millward A, et al (2002). Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome.
J Clin Endocrinol Metab,
87(6), 2606-2610.
Abstract:
Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome.
Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.
Abstract.
Author URL.
Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, Roosen S, Lingott-Frieg A, Tack CJ, Ellard S, Ryffel GU, et al (2001). A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young.
Hum Mol Genet,
10(19), 2089-2097.
Abstract:
A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young.
Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic beta-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic beta-cells, i.e. HNF-4alpha (MODY1), HNF-1alpha (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1beta (MODY5). Analyzing the transcription of the HNF-4alpha gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT-PCR this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1alpha, HNF-1beta and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4alpha gene.
Abstract.
Author URL.
Frayling TM, Menzel S, Wishart M, Vaxillaire M, Lindgren C, Tuomi T, Wang Y, Brown A, Bulman MP, Ellard S, et al (2001). A genome scan reveals heterogeneity among European families with maturity onset diabetes of the young.
DIABETOLOGIA,
44, A64-A64.
Author URL.
Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, O'Rahilly S, Frayling TM, Bell JI, Lathrop GM, et al (2001). A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.
Am J Hum Genet,
69(3), 553-569.
Abstract:
A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.
Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.
Abstract.
Author URL.
Mitchell SMS, Thomas H, Jaschkowitz K, Bulman MP, Frayling TM, Tack C, Ellard S, Ryffel GU, Hattersley AT (2001). A mutation of a novel splice variant of HNF-4a co-segregates with maturity-onset diabetes of the young (MODY).
DIABETOLOGIA,
44, A65-A65.
Author URL.
Gloyn AL, Desai M, Clark A, Holman RR, Levy JC, Frayling TM, Hattersley AT, Ashcroft SJH (2001). Calcium/calmodulin - Dependent protein kinase II gamma: Cloning, determination of genomic structure and screening for variants in subjects with type 2 diabetes.
DIABETES,
50, A236-A236.
Author URL.
Gloyn AL, Desai M, Clark A, Holman RR, Frayling TM, Hattersley AT, Ashcroft SJH (2001). Calcium/calmodulin dependent protein kinase II genes: Genomic structure and screening for variants in subjects with Type 2 diabetes.
DIABETOLOGIA,
44, A88-A88.
Author URL.
McCarthy MI, Hattersley AT, Walker M, Hitman GA, Levy JC, O'Rahilly S, Frayling TM, Bennett A, Smedley D, Menzel S, et al (2001). Genome scan linkage data from a large European family collection supports localisation of a type 2 diabetes susceptibility gene to chromosome 1q21-23.
DIABETES,
50, A27-A27.
Author URL.
Frayling TM, Wiltshire S, Walker M, Hitman GA, Levy JC, O'Rahilly S, Lathrop M, Menzel SM, McCarthy MI, Hattersley AT, et al (2001). Genome wide linkage analyses in subsets of young onset type 2 diabetes families from the diabetes (UK) warren 2 sibpair repository reveal loci on chromosomes 1, 5, 8, 10 and 22.
DIABETES,
50, A28-A28.
Author URL.
McCarthy MI, Hattersley AT, Walker M, Hitman GA, Levy JC, O'Rahilly S, Lathrop GM, Simecek N, Wishart M, Dhillon R, et al (2001). Linkage analysis in the Diabetes (UK) Warren 2 sibpair repository supports localisation of a type 2 diabetes susceptibility gene to chromosome 1q21-24.
DIABETOLOGIA,
44, A37-A37.
Author URL.
Evans JC, Frayling TM, Cassell PG, Saker PJ, Hitman GA, Walker M, Levy JC, O'Rahilly S, Rao PV, Bennett AJ, et al (2001). Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.
Am J Hum Genet,
69(3), 544-552.
Abstract:
Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.
Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.
Abstract.
Author URL.
Frayling TM, Hattersley AT (2001). The role of genetic susceptibility in the association of low birth weight with type 2 diabetes.
Br Med Bull,
60, 89-101.
Abstract:
The role of genetic susceptibility in the association of low birth weight with type 2 diabetes.
We suggest that altered fetal growth and type 2 diabetes may be two phenotypes of the same genotype - in other words the 'thrifty phenotype' is the result of a 'thrifty genotype'. Supporting this there is strong evidence that paternal factors and, therefore, genes influence fetal growth and that these paternal genes affecting fetal growth may also alter diabetes risk. Further study is needed to determine whether common gene variants can explain the association between reduced birth weight and increased risk of type 2 diabetes. If the genetic hypothesis is true, common diabetes genes are likely to have subtle effects on insulin secretion and/or action and, therefore, subtle effects on fetal growth. Large cohorts of infants and their parents will be required - probably in the region of thousands rather than hundreds - to identify gene variants that may explain the association between reduced birth weight and increased risk of type 2 diabetes. All previously described associations between birth weight and type 2 diabetes have required many hundreds of subjects and it is likely that the geneticists and the 'programmists' are trying to identify very subtle physiological effects.
Abstract.
Author URL.
Minton J, Hattersley A, Frayling T, Barrett T (2001). Variations in the WFS1 (Wolfram syndrome) gene are not associated with type 2 diabetes.
DIABETOLOGIA,
44, A95-A95.
Author URL.
Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, Bingham C, Hannemann M, Shepherd M, Ellard S, et al (2001). β-cell genes and diabetes: Molecular and clinical characterization of mutations in transcription factors.
Diabetes,
50(SUPPL. 1).
Abstract:
β-cell genes and diabetes: Molecular and clinical characterization of mutations in transcription factors
β-Cell transcription factor genes are important in the pathophysiology of the β-cell, with mutations in hepatocyte nuclear factor (HNF)-1α, HNF-4α, insulin promoter factor (IPF)-1, HNF-1β, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1α, 2% HNF-4α, 0% IPF-1, 1% HNF-1β, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients including 29 new families and 8 novel HNF-1α gene mutations. Mutations in the transactivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruption of this domain is necessary to result in diabetes. Mutations in the different transcription factors result in clinical heterogeneity. IPF-1 mutations are associated with a higher age at diagnosis (42.7 years) than HNF-1α (20.4 years), HNF-1β (24.2 years), or HNF-4α (26.3 years) gene mutations. Subjects with HNF-1β mutations, in contrast to the other transcription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF-1α mutations did not reveal genotype-phenotype correlations. In conclusion, mutations in transcription factors expressed in the β-cell are the major cause of MODY, and the phenotype clearly varies with the gene that is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.
Abstract.
Pearson ER, Velho G, Clark P, Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Froguel P, Hattersley AT, et al (2001). β-cell genes and diabetes: Quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1α and glucokinase mutations.
Diabetes,
50(SUPPL. 1).
Abstract:
β-cell genes and diabetes: Quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1α and glucokinase mutations
Mutations in the β-cell genes encoding the glycolytic enzyme glucokinase (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1α are the most common causes of maturity-onset diabetes of the young (MODY). Studying patients with mutations in these genes gives insights into the functions of these two critical β-cell genes in humans. We studied 178 U.K. and French MODY family members, including 45 GCK mutation carriers and 40 HNF-1α mutation carriers. Homeostasis model assessment of fasting insulin and glucose showed reduced β-cell function in both GCK (48% controls, P < 0.0001) and HNF-1α (42% controls, P < 0.0001). Insulin sensitivity was similar to that of control subjects in the GCK subjects (93% controls, P = 0.78) but increased in the HNF-1α subjects (134.5% controls, P = 0.005). The GCK patients showed a similar phenotype between and within families with mild lifelong fasting hyperglycemia (fasting plasma glucose [FPG] 5.5-9.2 mmol/l, interquartile [IQ] range 6.6-7.4), which declined slightly with age (0.017 mmol/l per year) and rarely required pharmacological treatment (17% oral hypoglycemic agents, 4% insulin). HNF-1α patients showed far greater variation in fasting glucose both between and within families (FPG 4.1-18.5 mmol/l, IQ range 5.45-10.4), with a marked deterioration with age (0.06 mmol/l per year), and 59% of patients required treatment with tablets or insulin. Proinsulin-to-insulin ratios are increased in HNF-1α subjects (29.5%) but not in GCK (18.5%) subjects. In an oral glucose tolerance test, the 0- to 120-min glucose increment was small in GCK patients (2.4 ± 1.8 mmol/l) but large in HNF-1α patients (8.5 ± 3.0 mmol/l, P < 0.0001). This comparison shows that the clear clinical differences in these two genetic subgroups of diabetes reflect the quantitative and qualitative differences in β-cell dysfunction. The defect in GCK is a stable defect of glucose sensing, whereas the HNF-1α mutation causes a progressive defect that alters β-cell insulin secretion directly rather than the sensing of glucose.
Abstract.
Bingham C, Ellard S, Allen L, Bulman M, Shepherd M, Frayling T, Berry PJ, Clark PM, Lindner T, Bell GI, et al (2000). Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta.
Kidney Int,
57(3), 898-907.
Abstract:
Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta.
BACKGROUND: the transcription factor hepatocyte nuclear factor (HNF)-1 beta functions as a homodimer or as a heterodimer with the structurally related protein HNF-1 alpha. Both are expressed sequentially in rat kidney development, with HNF-1 beta being detected from the earliest inductory phases. HNF-1 beta gene mutations are associated with a unique disorder characterized by maturity-onset diabetes of the young (MODY) and early-onset and progressive nondiabetic renal dysfunction, which may lead to chronic renal failure. METHODS: the HNF-1 beta gene was screened for mutations in six subjects with early-onset diabetes and a history of renal dysfunction in the subjects or their families. RESULTS: a novel frameshift mutation in exon 4 of the HNF-1 beta gene and a deletion of CCTCT at codons 328 to 329 were detected in one subject. She was diagnosed as diabetic at the age of 21 in her second pregnancy. Glucose tolerance rapidly deteriorated over 18 months as a result of beta-cell dysfunction. The HNF-1 beta mutation arose de novo on a paternal chromosome and cosegregated with renal abnormalities in her family. The proband had bilateral small cysts in normal-sized kidneys and a reduced creatinine clearance of 66 mL/min (NR 80-120). Her first pregnancy was terminated at 17 weeks following an ultrasound diagnosis of bilateral, nonfunctioning cystic kidneys. Her first-born child had a small multicystic, dysplastic right kidney and a dysplastic left kidney with a reduced creatinine clearance (40 mL/min per 1.73 m2). Histologic examination of the large (5.8 vs. 1.4 g), polycystic fetal kidneys showed no normal nephrogenesis. CONCLUSIONS: These studies indicate that HNF-1 beta plays a central role in normal kidney development and pancreatic beta-cell function, and suggest that one mechanism by which HNF-1 beta gene mutations may cause renal dysfunction are by their effects on nephron development.
Abstract.
Author URL.
Huxtable SJ, Saker PJ, Haddad L, Walker M, Frayling TM, Levy JC, Hitman GA, O'Rahilly S, Hattersley AT, McCarthy MI, et al (2000). Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.
Diabetes,
49(1), 126-130.
Abstract:
Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.
Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.
Abstract.
Author URL.
Evans JC, Frayling TM, Ellard S, Gutowski NJ (2000). Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31.
Hum Genet,
106(6), 636-638.
Abstract:
Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31.
Duane's syndrome is a congenital abnormality of eye movement, which may be inherited as an autosomal dominant trait but usually occurs sporadically. Genetic mapping in a Mexican family has recently identified a locus for Duane's syndrome within a 17.8-cM region of chromosome 2q31. The region was flanked by the microsatellite markers D2S2330 and D2S364. We performed linkage and haplotype analysis in a four-generation UK family with autosomal dominant transmission of Duane's syndrome. Linkage to 2q31 was confirmed with a maximum logarithm of differences (lod) score of 3.3 at theta = 0. The genetic interval was reduced to an 8.8-cM region between markers D2S326 and D2S364 that includes the candidate homeobox D gene cluster.
Abstract.
Author URL.
Cassell PG, Saker PJ, Huxtable SJ, Kousta E, Jackson AE, Hattersley AT, Frayling TM, Walker M, Kopelman PG, Ramachandran A, et al (2000). Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin.
Diabetologia,
43(12), 1558-1564.
Abstract:
Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin.
AIMS/HYPOTHESIS: Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (-55 c-->t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations. METHODS: the -55 c-->t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes. RESULTS: in South Indian and European parent-offspring trios there was no preferential transmission of either allele at the -55 c-->t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039). CONCLUSION/INTERPRETATION: the consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females.
Abstract.
Author URL.
Lynn S, Hattersley AT, McCarthy MI, Frayling TM, Turnbull DM, Walker M (2000). Intermediate expansions of a X25/frataxin gene GAA repeat and type II diabetes: assessment using parent-offspring trios.
Diabetologia,
43(3), 384-385.
Author URL.
Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayers S, Shepherd M, Clark P, Millward A, et al (2000). Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.
J Clin Invest,
106(5).
Author URL.
Turnpenny P, Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Hattersley AT, Ellard S (2000). Multiple vertebral segmentation defects in spondylocostal dysostosis are caused by mutations in the human Delta homologue DLL3, a somite boundary gene in the Notch signalling pathway.
JOURNAL OF MEDICAL GENETICS,
37, S24-S24.
Author URL.
Tumpenny PD, Bulman MP, Kusumi K, Frayling TM, Duncan J, McKeown C, Garrett C, Krumlauf R, Hattersley AT, Ellard S, et al (2000). Mutations in the human <i>Delta</i> homologue, <i>DLL3</i>, a <i>Notch</i> signaling pathway gene, disrupt somite boundary formation in spondylocostal dysostosis, which demonstrates both clinical and genetic heterogeneity.
AMERICAN JOURNAL OF HUMAN GENETICS,
67(4), 13-13.
Author URL.
Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD, et al (2000). Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.
Nat Genet,
24(4), 438-441.
Abstract:
Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.
Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance reported. Autosomal recessive SD maps to a 7.8-cM interval on chromosome 19q13.1-q13.3 that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (Dll3). Dll3 is mutated in the X-ray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial
Abstract.
Author URL.
Frayling TM, McCarthy MI, Walker M, Levy JC, O'Rahilly S, Hitman GA, Rao PV, Bennett AJ, Jones EC, Menzel S, et al (2000). No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.
J Clin Endocrinol Metab,
85(2), 853-857.
Abstract:
No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.
Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.
Abstract.
Author URL.
Ellard S, Bulman MP, Frayling TM, Shepherd M, Hattersley AT (2000). Proposed mechanism for a novel insertion/deletion frameshift mutation (I414G415ATCG-->CCA) in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene which causes maturity-onset diabetes of the young (MODY).
Hum Mutat,
16(3).
Abstract:
Proposed mechanism for a novel insertion/deletion frameshift mutation (I414G415ATCG-->CCA) in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene which causes maturity-onset diabetes of the young (MODY).
Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes (NIDDM) characterized by an early age of diagnosis (usually < 25 years) and an autosomal dominant mode of inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1alpha) [MODY3] gene represent the most common cause of MODY in the UK and a common cause of MODY in many other populations. Sixty-three different mutations have been described in a total of 112 families worldwide. This report describes two families, not known to be related, who carry a novel insertion/deletion mutation (I414G415ATCG-->CCA) and a 6bp intronic deletion of the HNF-1alpha gene in cis. We propose that the insertion/deletion mutation has arisen by formation of a hairpin loop due to the presence of a quasi-palindromic sequence, followed by insertion of CC and deletion of TCG resulting in the increased stability of the hairpin loop.
Abstract.
Author URL.
Vaxillaire M, Chèvre JC, Benmezroua Y, Lecoeur C, Dina C, Costa A, Conget I, Hansen T, Frayling T, Hattersley AT, et al (2000). Search for new genetic determinants of early-onset type 2 diabetes:: Genetic and clinical dissection of MODY-like inherited diabetes.
DIABETOLOGIA,
43, A81-A81.
Author URL.
McCarthy MI, Hattersley AT, Walker M, Hitman GA, Levy JC, O'Rahilly S, Lathrop GM, Simecek N, Wishart M, Dhillon R, et al (2000). The BDA Warren Type 2 Diabetes Sibpair Repository: Susceptibility regions identified by genome scan of 439 European families.
DIABETOLOGIA,
43, A50-A50.
Author URL.
McCarthy M, Hattersley A, Walker M, Hitman G, Levy J, O'Rahilly S, Lathrop M, Simecek N, Wishart M, Dhillon R, et al (2000). The British Diabetic Association Warren Type 2 Diabetes Sibpair Repository: Interim report on a genome-wide scan for linkage in 439 European sibpair families.
DIABETES,
49, A199-A199.
Author URL.
Frayling TM, Evans JC, Ellard S, Hattersley AT (2000). Transmission disequilibrium at the calpain10/NIDDM1 gene in UK Caucasian type 2 diabetes parent-offspring trios.
DIABETES,
49, A8-A8.
Author URL.
Eliard S, Bingham C, Allen LIS, Bulman MP, Frayling TM, Shepherd M, Berry P, Hattersley AT (1999). A 5bp deletion in the hepatocyte nuclear factor 1-beta gene is associated with diabetes and renal dysfunction.
JOURNAL OF MEDICAL GENETICS,
36, S62-S62.
Author URL.
Hattersley AT, Bingham C, Shepard M, Allen LI, Berry P, Bulman M, Frayling TM, Ellard S (1999). A frameshift mutation in hepatocyte nuclear factor 1β cause diabetes by β cell dysfunction and renal dysfunction by abnormal nephron development.
DIABETES,
48, A33-A33.
Author URL.
Turnpenny PD, Bulman MP, Frayling TM, Abu-Nasra TK, Garrett C, Hattersley AT, Ellard S (1999). A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3.
Am J Hum Genet,
65(1), 175-182.
Abstract:
A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3.
In spondylocostal dysostosis (SD), vertebral-segmentation defects are associated with rib anomalies. This results in short-trunk short stature, nonprogressive kyphoscoliosis, and radiological features of multiple hemivertebrae and rib fusions. SD can be familial, and both autosomal dominant and autosomal recessive (AR) inheritance have been reported, but no genes have been identified or localized for nonsyndromic SD in humans. We performed genomewide scanning by homozygosity mapping in a large consanguineous ARSD Arab Israeli family with six definitely affected members. Significant linkage was found to chromosome 19q13, with a LOD score of 6.9. This was confirmed in a second Pakistani family with three affected members, with a LOD score of 2.4. The combined-haplotype data identify a critical region between D19S570 and D19S908, an interval of 8.5 cM on 19q13.1-19q13.3. This is the first study to localize a gene for nonsyndromic SD. ARSD is clinically heterogeneous and is likely to result from mutations in developmental genes or from regulating transcription factors. Identification of these genes will improve the understanding of the molecular processes contributing to both normal and abnormal human vertebral development.
Abstract.
Author URL.
Ellard S, Bulman MP, Frayling TM, Allen LI, Dronsfield MJ, Tack CJ, Hattersley AT (1999). Allelic drop-out in exon 2 of the hepatocyte nuclear factor-1alpha gene hinders the identification of mutations in three families with maturity-onset diabetes of the young.
Diabetes,
48(4), 921-923.
Author URL.
Frayling TM, Evans JC, Allen LIS, Macfarlane W, Docherty K, Milward A, Demaine A, Wilkin TJ, Ayres S, Clark P, et al (1999). Functional missense mutations in the insulin promoter factor 1 (IPF1) gene predispose to type 2 diabetes.
DIABETES,
48, A33-A33.
Author URL.
Lynn S, Hattersley AT, McCarthy MI, Frayling TM, Turnbull DM, Walker M (1999). Intermediate GAA repeat expansions of the X25/frataxin gene in type 2 diabetes.
DIABETOLOGIA,
42, A120-A120.
Author URL.
Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayres S, Shepherd M, Clark P, Millward A, et al (1999). Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.
J Clin Invest,
104(9), R33-R39.
Abstract:
Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.
The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic beta cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human beta-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25-53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation.
Abstract.
Author URL.
Frayling TM, Walker M, McCarthy MI, Evans JC, Allen LI, Lynn S, Ayres S, Millauer B, Turner C, Turner RC, et al (1999). Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes.
Diabetes,
48(12), 2475-2479.
Abstract:
Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes.
The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K. only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.
Abstract.
Author URL.
Frayling TM, Mccarthy M, Walker M, Evans JC, Allen LIS, Ayres S, Ellard S, Hattersley AT (1999). The collection of Type 2 diabetics with both parents alive to facilitate the identification of susceptibility genes: the BDA Warren 2 Type 2 diabetes Trios.
DIABETES,
48, A402-A402.
Author URL.
Huxtable SJ, Saker PJ, Walker M, Frayling TM, Levy JC, Hitman GA, O'Rahilly S, Hattersley AT, McCarthy MI (1999). The insulin gene and type 2 diabetes: Evidence for linkage and association mediated exclusively by paternally-derived alleles.
DIABETOLOGIA,
42, A20-A20.
Author URL.
McCarthy MI, Saker PJ, Hattersley AT, Frayling T, Walker M, Turner R, O'Rahilly S, Hitman G, Rao PS (1999). Type 2 diabetes and the human homolog of the rat insulin resistance gene, CD36: No linkage or association in Europeans.
DIABETOLOGIA,
42, A118-A118.
Author URL.
Saker PJ, Huxtable AT, Hattersley AT, Walker M, Frayling T, Kousta E, McCarthy M (1999). Variation in the gene for the skeletal muscle uncoupling protein (UCP3): a novel promoter variant influencing fat distribution.
DIABETOLOGIA,
42, A119-A119.
Author URL.
Saker P, Hattersley A, Walker M, Frayling T, Wahid F, Cooper L, Scott J, Aitman T, Mccarthy MI (1999). Variation in the human homolog of the rodent insulin-resistance gene, <i>Cd36</i>, and susceptibility to type 2 diabetes.
DIABETES,
48, A406-A406.
Author URL.
Frayling T, Ellard S, Grove J, Walker M, Hattersley AT (1998). C282Y mutation in HFE (haemochromatosis) gene and type 2 diabetes.
Lancet,
351(9120), 1933-1934.
Author URL.
Frayling T, Ellard S, Ayres S, Ayres R, Hattersley AT (1998). Haemochromatosis and type 2 diabetes - Reply.
LANCET,
352(9133), 1068-1068.
Author URL.
Beards F, Frayling T, Bulman M, Horikawa Y, Allen L, Appleton M, Bell GI, Ellard S, Hattersley AT (1998). Mutations in hepatocyte nuclear factor 1beta are not a common cause of maturity-onset diabetes of the young in the U.K.
Diabetes,
47(7), 1152-1154.
Author URL.
Frayling T, Beards F, Bulman M, Appleton M, Ellard S, Hattersley AT (1998). Mutations in the hepatocyte nuclear factor 1-beta (HNF-1β) gene are not a common cause of UK maturity onset diabetes of the young (MODY).
DIABETES,
47, A173-A173.
Author URL.
Hattersley A, Appleton M, Ellard S, Frayling T, Bulman M, Tack C, Clark P (1998). Phenotypic determinants in hepatocyte nuclear factor 1α (HNf1α) mutations.
DIABETES,
47, A179-A179.
Author URL.
Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT (1997). A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young.
Diabetologia,
40(7), 859-862.
Abstract:
A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young.
Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised bylan early age of onset (< 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3]. A nonsense mutation in the HNF-4 alpha gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at theta = 0) for mutations in the coding region of the HNF-4 alpha gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4 alpha gene.
Abstract.
Author URL.
Frayling T, Bulman M, Ellard S, Appleton M, Dronsfield MJ, Bain SC, Bell GI, Hattersley AT (1997). A mutational hotspot in the poly-C tract of exon 4 of the hepatic nuclear factor 1alpha gene; Screening in Maturity Onset Diabetes of the Young.
DIABETOLOGIA,
40, 18-18.
Author URL.
Frayling TM, Bulman MP, Appleton M, Hattersley AT, Ellard S (1997). A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes.
Hum Genet,
101(3), 351-354.
Abstract:
A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes.
Non-insulin dependent diabetes (NIDDM) is a polygenic heterogeneous disorder of glucose homeostasis. Maturity-onset diabetes of the young (MODY) is a monogenic subtype of NIDDM characterised by early-onset (< 25 years) and autosomal dominant inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1 alpha) gene have recently been shown to cause MODY. The incidence of mutations in this gene in MODY and late-onset NIDDM is not known. We have developed a rapid specific polymerase chain reaction test for HNF-1 alpha mutations; this test involves the use of fluorescently labelled forward primers and modified reverse primers to detect length polymorphisms resulting from frameshift mutations. With this method, we have screened 102 MODY probands, viz. 60 defined according to strict diagnostic criteria (autosomal dominant inheritance and at least one member diagnosed age < 25 years) and 95 late-onset NIDDM probands (diagnosed 35-70 years with > or = 1 affected relative), for the presence of 9 known HNF-1 alpha frameshift mutations, including 6 that occur at two sites for recurring mutation (residues 291/292 and 379). Mutations were detected in 11 of the strictly defined MODY probands and one mutation was also found in a single subject with early-onset NIDDM but no family history of the disease. The HNF-1 alpha frameshift mutations were not detected in any late-onset NIDDM subjects, suggesting these mutations do not have a major role in the pathogenesis of NIDDM. Our results indicate that the prevalence of the nine frameshift mutations in strictly defined UK MODY is 18%, with the P291fsinsC mutation alone having a frequency of 13%.
Abstract.
Author URL.
Appleton M, Ellard S, Bulman M, Frayling T, Page R, Hattersley AT (1997). Clinical characteristics of HNF1 alpha (MODY3) and glucokinase mutations.
DIABETOLOGIA,
40, 628-628.
Author URL.
Hattersley AT, Appleton M, Smith SM, Burrows JA, Ellard S, Frayling T, Bulman M, Clark PM (1997). Hepatic nuclear factor 1 alpha mutations result in beta-cell dysfunction.
DIABETOLOGIA,
40, 634-634.
Author URL.
Frayling T, Bulman M, Ellard S, Appleton M, Dronsfield M, Bain S, Hattersley A (1997). Hepatic nuclear factor 1-alpha (HNF-1 alpha) gene mutations are the commonest cause of maturity onset diabetes of the young in the UK.
DIABETES,
46, 683-683.
Author URL.
Ellard S, Bulman MP, Frayling TM, Beards FE, Appleton M, Hattersley AT (1997). Mutation analysis in maturity-onset diabetes of the young (MODY).
JOURNAL OF MEDICAL GENETICS,
34, SP15-SP15.
Author URL.
Bulman MP, Frayling T, Ellard S, Appleton M, Dronsfield MJ, Bell GI, Bain SC, Hattersley AT (1997). Mutations in the hepatic nuclear factor 1 alpha in maturity-onset diabetes of the young.
DIABETOLOGIA,
40, 618-618.
Author URL.
Frayling TM, Bulamn MP, Ellard S, Appleton M, Dronsfield MJ, Mackie AD, Baird JD, Kaisaki PJ, Yamagata K, Bell GI, et al (1997). Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K.
Diabetes,
46(4), 720-725.
Abstract:
Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K.
Mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene have recently been shown to cause maturity-onset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1alpha gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (
Abstract.
Author URL.
