Publications by year
In Press
Duckworth A, Gibbons MA, Beaumont RN, Wood AR, Almond H, Lunnon K, Lindsay MA, Scotton CJ, Tyrrell J (In Press). A Mendelian randomisation study of smoking causality in IPF compared with COPD.
Abstract:
A Mendelian randomisation study of smoking causality in IPF compared with COPD
AbstractIn a normal year, the fatal lung disease Idiopathic Pulmonary Fibrosis (IPF) accounts for ∼1% of UK deaths. Smoking is a recognised risk factor for IPF but the question of causality remains unanswered. Here, we used data from the UK Biobank (UKBB) and the well-established genetic technique of Mendelian randomisation (MR) methods to investigate whether smoking is causal for IPF compared with COPD, where causality is established.We looked at observational associations in unrelated Europeans, with 871 IPF cases, 11,413 COPD cases and 366,942 controls. We performed analyses using one-sample MR to test for inferred smoking causality in ever smokers using genetic variants that have a previously demonstrated association with smoking heaviness.Strong associations between disease status and ever having smoked were found in both IPF (OR = 1.52; 95%CI:1.32-1.74; P=2.4×10−8) and COPD (OR= 5.77; 95%CI:5.48-6.07; P<1×10−15). Using MR, a one allele increase in smoking volume genetic risk score was associated with higher odds of COPD in ever smokers, (OR = 4.32; 95%CI:3.37-5.54; P<1×10−15), but no association was seen in IPF (OR=0.55; 95%CI: 0.17-1.81; P=0.33). No association was found between the genetic risk score and disease prevalence in never smokers with IPF (OR = 1.00; 95%CI:0.98-1.02; P=1.00) or COPD (OR = 1.00; 95%CI:0.99-1.01; P=0.53).Although both IPF and COPD are observationally associated with smoking, our analysis provides evidence inferring that the association is causal in COPD but there is no such evidence in IPF. This suggests that other environmental exposures also need consideration in IPF.
Abstract.
Green HD, Jones A, Evans JP, Wood AR, Beaumont RN, Tyrrell J, Frayling TM, Smith C, Weedon MN (In Press). 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.
Abstract.
Bailey S, Green H, Merriel S, Oram R, Thirlwell C, Ruth K, Tyrrell J, Weedon M (In Press). Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank. British Journal of Cancer
Weedon MN, Jackson L, Harrison JW, Ruth KS, Tyrrell J, Hattersley AT, Wright CF (In Press). Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing.
Abstract:
Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing
ABSTRACTObjectivesTo determine the analytical validity of SNP-chips for genotyping very rare genetic variants.DesignRetrospective study using data from two publicly available resources, the UK Biobank and the Personal Genome Project.SettingResearch biobanks and direct-to-consumer genetic testing in the UK and USA.Participants49,908 individuals recruited to UK Biobank, and 21 individuals who purchased consumer genetic tests and shared their data online via the Personal Genomes Project.Main outcome measuresWe assessed the analytical validity of genotypes from SNP-chips (index test) with sequencing data (reference standard). We evaluated the genotyping accuracy of the SNP-chips and split the results by variant frequency. We went on to select rare pathogenic variants in the BRCA1 and BRCA2 genes as an exemplar for detailed analysis of clinically-actionable variants in UK Biobank, and assessed BRCA-related cancers (breast, ovarian, prostate and pancreatic) in participants using cancer registry data.ResultsSNP-chip genotype accuracy is high overall; sensitivity, specificity and precision are all >99% for 108,574 common variants directly genotyped by the UK Biobank SNP-chips. However, the likelihood of a true positive result reduces dramatically with decreasing variant frequency; for variants with a frequency <0.001% in UK Biobank the precision is very low and only 16% of 4,711 variants from the SNP-chips confirm with sequencing data. Results are similar for SNP-chip data from the Personal Genomes Project, and 20/21 individuals have at least one rare pathogenic variant that has been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, the overall performance metrics of the SNP-chips in UK Biobank are sensitivity 34.6%, specificity 98.3% and precision 4.2%. Rates of BRCA-related cancers in individuals in UK Biobank with a positive SNP-chip result are similar to age-matched controls (OR 1.28, P=0.07, 95% CI: 0.98 to 1.67), while sequence-positive individuals have a significantly increased risk (OR 3.73, P=3.5×10−12, 95% CI: 2.57 to 5.40).ConclusionSNP-chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.SUMMARY BOXSection 1: What is already known on this topicSNP-chips are an accurate and affordable method for genotyping common genetic variants across the genome. They are often used by direct-to-consumer (DTC) genetic testing companies and research studies, but there several case reports suggesting they perform poorly for genotyping rare genetic variants when compared with sequencing.Section 2: What this study addsOur study confirms that SNP-chips are highly inaccurate for genotyping rare, clinically-actionable variants. Using large-scale SNP-chip and sequencing data from UK Biobank, we show that SNP-chips have a very low precision of <16% for detecting very rare variants (i.e. the majority of variants with population frequency of <0.001% are false positives). We observed a similar performance in a small sample of raw SNP-chip data from DTC genetic tests. Very rare variants assayed using SNP-chips should not be used to guide health decisions without validation.
Abstract.
Tyrrell J, O'Loughlin J, Casanova F, Bowden J, Freathy R, Watkins E (In Press). BMI and Well-being in people of East Asian and European Ancestry: a Mendelian Randomisation Study.
Translational PsychiatryAbstract:
BMI and Well-being in people of East Asian and European Ancestry: a Mendelian Randomisation Study
Previous studies have linked higher Body Mass Index (BMI) to lower subjective well-being in adult European ancestry populations. However, our understanding of these relationships across different populations is limited. Here, we investigated the association between BMI and well-being in people of a) East Asian and b) European ancestry in the China Kadoorie Biobank (CKB) and UK Biobank (UKB), respectively. Mendelian randomisation (MR) methods were used to test the relationship between BMI with a) health satisfaction and b) life satisfaction. One-sample MR enabled us to test effects in men and women separately and to test the role of cultural contexts by stratifying our analyses by urban and rural home location in both China and the UK. Further, we implemented a control function method to test the linearity of the BMI-well-being relationship. We found evidence of different associations between BMI and well-being in individuals of East Asian versus European ancestry. For example, a genetically-instrumented higher BMI tentatively associated with higher health satisfaction in people of East Asian ancestry, especially in females (ß: 0.041, 95% CI: 0.002, 0.081). In contrast, there was a robust inverse association between higher genetically-instrumented BMI and health satisfaction in all European ancestry UKB participants (ß: -0.183, 95% CI: -0.200, -0.165, Pdifference
Abstract.
Karageorgiou V, Casanova F, O'Loughlin J, Green H, McKinley TJ, Bowden J, Tyrrell J (In Press). Body Mass Index and Inflammation in Depression and Treatment-Resistant Depression: a Mendelian Randomization Study.
Abstract:
Body Mass Index and Inflammation in Depression and Treatment-Resistant Depression: a Mendelian Randomization Study
Abstract
. Introduction: Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological modalities is considered inadequate and symptoms persist (treatment-resistant depression (TRD)). We aim to investigate inflammation, proxied by C-reactive protein (CRP) levels, and body mass index (BMI) as putative causal risk factors for depression and subsequent treatment resistance, leveraging genetic
information to avoid confounding via Mendelian Randomization (MR).
Methods: We used the European UK Biobank subcohort (n = 451, 025), the mental health questionnaire (MHQ) and clinical records. For treatment resistance, a previously curated phenotype based on GP records and prescription data was employed. We applied univariable and multivariable MR models to genetically predict the exposures and assess their causal contribution to a range of depression outcomes. We used weak and pleiotropy, robust estimation techniques within univariable, multivariable and mediation MR models in order to address
our research question with maximum rigour. In addition, we developed a novel statistical procedure to apply pleiotropy robust multivariable MR to one sample data and employed an unfamiliar bootstrap procedure to accurately quantify estimate uncertainty in mediation analysis which outperforms
standard approaches.
Results: in univariable MR models, genetically predicted BMI was positively associated with depression outcomes, including MDD and TRD, with a larger magnitude in women and with age acting
as a moderator of the effect of BMI on PHQ9 (p = 0.011). Multivariable MR analyses suggested an independent causal effect of BMI on TRD not through CRP. Our mediation analyses suggested
that the effect of CRP on PHQ9 was partly mediated by BMI. Individuals with TRD (n = 2, 199) observationally had higher CRP and BMI compared with individuals with MDD alone and healthy
controls. A positive causal association was noted for both the exposures, but in multivariable analyses only BMI retained statistical significance at the 5% level.
Discussion: Our work supportst the assertion BMI exerts a causal effect on a range of clinical and questionnaire-based depression phenotypes, with the effect being stronger in women and in younger individuals. We show that this effect is independent of inflammation proxied by CRP levels as the effects of CRP do not persist when jointly estimated with BMI. This is consistent with previous evidence suggesting that overweight contributed to depression even in the absence of any metabolic consequences. It appears that BMI exerts an effect on TRD that persists when we account for BMI influencing MDD.
Abstract.
Oram RA, Weedon M, Wood A, Beaumont R, Tyrrell J (In Press). Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident
Diagnosis. Diabetes Care
Howe LD, Kanayalal R, Beaumont RN, Davies AR, Frayling TM, Harrison S, Jones SE, Sassi F, Wood AR, Tyrrell J, et al (In Press). 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.
Abstract.
Duckworth A, Gibbons MA, Allen RJ, Almond H, Beaumont RN, Wood AR, Lunnon K, Lindsay MA, Wain LV, Tyrrell J, et al (In Press). Evidence that Telomere Length is Causal for Idiopathic Pulmonary Fibrosis but not Chronic Obstructive Pulmonary Disease: a Mendelian Randomisation Study.
Abstract:
Evidence that Telomere Length is Causal for Idiopathic Pulmonary Fibrosis but not Chronic Obstructive Pulmonary Disease: a Mendelian Randomisation Study
SummaryBackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in ∼30% of cases, and a majority relate to telomere maintenance. Prematurely shortened leukocyte telomere length has also been associated with IPF, as well as chronic obstructive pulmonary disease (COPD), a disease with a similar demographic and shared risk factors. Using Mendelian randomisation (MR), our study aimed to determine whether short telomeres cause IPF or COPD.MethodsWe performed an MR study for telomere length causality in IPF and COPD with up to 1,369 IPF cases, 14,103 COPD cases and 435,866 controls of European ancestry in UK Biobank. Initial studies using polygenic risk scores followed by two-sample MR analyses were carried out using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort of 2,668 IPF cases and 8,591 controls and a COPD cohort of 15,256 cases and 47,936 controls.FindingsMeta-analysis of the two-sample MR results provided evidence that shorter telomeres cause IPF, with a genetically instrumented one standard deviation shorter telomere length associated with 5.81 higher odds of IPF ([95% CI: 3.56-9.50], P=2.19×10−12. Despite being an age-related lung disease with overlapping risk, there was no evidence that telomere length caused COPD (OR 1.07, [95% CI 0.90-1.27], P = 0.46).InterpretationCellular senescence is hypothesised as a major driving force in both IPF and COPD; telomere shortening may be a contributory factor in IPF, suggesting divergent mechanisms in COPD. This enables greater focus in telomere-related diagnostics, treatments and the search for a cure in IPF. Therapies manifesting improvements in telomere length, including safe telomere activation therapy, may warrant investigation.
Abstract.
Thompson WD, Beaumont RN, Kuang A, Warrington NM, Ji Y, Tyrrell J, Wood AR, Scholtens D, Knight BA, Evans DM, et al (In Press). 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.
Abstract.
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
Abstract.
Thompson WD, Beaumont RN, Kuang A, Warrington NM, Ji Y, Tyrrell J, Wood AR, Scholtens D, Knight BA, Evans DM, et al (In Press). 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.
Abstract.
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
Duckworth A, Ruth KS, Prague JK, Russell A-M, Almond H, Conway J, Beaumont RN, Wood AR, Martin S, Lunnon K, et al (In Press). Study of the associations between short telomeres, sex hormones and pulmonary fibrosis.
Abstract:
Study of the associations between short telomeres, sex hormones and pulmonary fibrosis
AbstractBackgroundPulmonary fibrosis (PF) is an incurable fibrotic lung disease with limited treatment options and a high mortality. Evidence is growing that short telomeres cause both heritable and idiopathic pulmonary fibrosis (IPF). Based on survival data, we hypothesised that sex hormones are protective against premature telomere attrition and could influence PF disease onset and/or progression.MethodsAssociations between IPF, sex hormone concentrations and measured leukocyte telomere length (LTL) were examined for unrelated UK Biobank participants of European ancestry with a diagnosis of IPF (415 females, 718 males) against controls (204,321 females, 174,254 males). Polygenic risk scores were used to explore causality between sex hormone indices, LTL and disease.FindingsStrong associations were found between IPF and LTL. For females, higher odds of having IPF was associated with early menopause and premature ovarian failure. Menopause age correlated positively with both age of IPF diagnosis and age of death. For males, IPF prevalence and stages of disease were associated with serum bioavailable testosterone concentrations. For both sexes, evidence of lower concentrations of sex hormones was associated with shorter LTL. Genetic analysis also inferred bi-directional causal links between sex hormone binding globulin concentration, which impacts free testosterone concentration, and LTL in males.InterpretationOur findings suggest that higher sex hormone concentrations protect against IPF onset and progression, possibly by slowing telomere shortening. Hormonal supplementation may delay or prevent disease onset for those with telomere-associated PF risk and improve disease prognosis. This warrants further exploration in a randomised controlled trial.FundingMedical Research Council.
Abstract.
Gillett AC, Hagenaars SP, Casanova F, Young KG, Green H, Lewis CM, Tyrrell J (In Press). The impact of major depressive disorder on glycaemic control in type 2 diabetes: a cohort study using UK Biobank primary care records.
Abstract:
The impact of major depressive disorder on glycaemic control in type 2 diabetes: a cohort study using UK Biobank primary care records
AbstractBackgroundThis study evaluates longitudinal associations between glycaemic control (mean and within-patient variability of glycated haemaglobin (HbA1c) levels) in individuals with type 2 diabetes (T2D) and major depressive disorder (MDD).MethodsIn UK Biobank (UKB), T2D was defined using self-report, linked primary care records, prescription records and hospital episode statistics, then validated using polygenic scores. Repeated HbA1c measurements were extracted from primary care records and baseline UKB biomarker measures, and used as the outcome in mixed effects models to investigate the association between MDD and glycaemic control over a maximum 10-year T2D disease duration. The exposure investigated was MDD, with subgroups defined by the relative timings of MDD and T2D diagnoses (no MDD, MDD diagnosis pre-T2D or post-T2D).Multiple imputation (n=9264) and complete case (n=4233) analyses were performed.ResultsThe T2D diagnostic criteria were robustly associated with T2D polygenic scores. Using mixed effect models and multiple imputation (7.6 year median follow-up), temporal trends in mean HbA1c did not differ by MDD subgroup. Within-patient variability in HbA1c was 1.14 (95% CI: 1.12-1.16) times higher in UKB participants diagnosed with MDD after T2D compared those with no MDD diagnosis. Complete case analyses results differed, but the substantial evidence against missingness being completely at random, suggests that complete case analysis will be biased.ConclusionsThese findings suggest closer monitoring to improve T2D control is important in individuals who develop MDD after T2D diagnosis. Further, the study highlights the importance of correctly accounting for missing data.Key messagesMajor depressive disorder (MDD) is associated with poorer glycaemic control and an increased risk of complications and mortality in individuals with type 2 diabetes (T2D). Research suggests that individuals diagnosed with MDD after T2D (post-T2D MDD) may be driving these associations, but the effect of diagnostic order on glycaemic control has not been investigated longitudinally.Using UK Biobank primary care records, we investigated whether post-T2D MDD is associated with poorer glycaemic control over the 10 years following a T2D diagnosis, as measured by mean HbA1c trends and within-patient HbA1c variability.Individuals with post-T2D MDD had greater within-patient variability in HbA1c compared to those with no MDD diagnosis, indicating poorer glycaemic control, but no difference in mean HbA1c was found. Individuals with pre-existing MDD had similar glycaemic control to those with no MDD.Results suggest the importance of considering within-patient variability in HbA1c, in addition to the mean, when investigating glycaemic control over time, and highlight the role of the relative timing of diagnosis for MDD and T2D in glycaemic control.
Abstract.
Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM, et al (In Press). The penetrance of age-related monogenic disease depends on ascertainment context.
Abstract:
The penetrance of age-related monogenic disease depends on ascertainment context
AbstractBACKGROUNDAccurate penetrance of monogenic disorders is often unknown due to a phenotype-first approach to genetic testing. Here, we use a genotype-first approach in four large cohorts with different ascertainment contexts to accurately estimate penetrance of the three commonest causes of monogenic diabetes, Maturity Onset Diabetes of the Young (MODY). We contrast HNF1A-MODY / HNF4A-MODY which causes an age-related progressive diabetes and GCK-MODY, which causes life-long mild hyperglycaemia.METHODSWe analysed clinical and genetic sequencing data from four different cohorts: 1742 probands referred for clinical MODY testing; 2194 family members of the MODY probands; 132,194 individuals from an American hospital-based cohort; and 198,748 individuals from a UK population-based cohort.RESULTSAge-related penetrance of diabetes for pathogenic variants in HNF1A and HNF4A was substantially lower in the clinically unselected cohorts compared to clinically referred probands (ranging from 32% to 98% at age 40yrs for HNF1A, and 21% to 99% for HNF4A). The background rate of diabetes, but not clinical features or variant type, explained the reduced penetrance in the unselected cohorts. In contrast, penetrance of mild hyperglycaemia for pathogenic GCK variants was similarly high across cohorts (ranging from 89 to 97%) despite substantial variation in the background rates of diabetes.CONCLUSIONSAscertainment context is crucial when interpreting the consequences of monogenic variants for age-related variably penetrant disorders. This finding has important implications for opportunistic screening during genomic testing.
Abstract.
Weedon M, Jackson L, Harrison J, Ruth K, Tyrrell J, Hattersley A, Wright C (In Press). Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation. BMJ: British Medical Journal
Martin S, Tyrrell J, Thomas EL, Bown MJ, Wood AR, Beaumont RN, Tsoi LC, Stuart PE, Elder JT, Law P, et al (In Press). Using genetics to uncouple higher adiposity from its adverse metabolic effects and understand its role in metabolic and non-metabolic disease.
Abstract:
Using genetics to uncouple higher adiposity from its adverse metabolic effects and understand its role in metabolic and non-metabolic disease.
Abstract
. To understand the consequences of higher adiposity uncoupled from its adverse metabolic effects, we selected 37 diseases associated with obesity and genetic variants associated with different aspects of excess weight including metabolically “favourable adiposity” (FA) and “unfavourable adiposity” (UFA). Mendelian randomisation (MR) identified two sets of diseases. First, 12 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, including colorectal and ovarian cancer, and gout. Second, 7 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) is likely a cause. Here MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, were both associated with higher disease risk, including osteoarthritis and venous thromboembolism. Individuals with high BMI are at higher risk of some diseases despite being relatively metabolically healthy.
Abstract.
2023
Power GM, Tobias JH, Frayling TM, Tyrrell J, Hartley AE, Heron JE, Davey Smith G, Richardson TG (2023). Age-specific effects of weight-based body size on fracture risk in later life: a lifecourse Mendelian randomisation study.
Eur J Epidemiol,
38(7), 795-807.
Abstract:
Age-specific effects of weight-based body size on fracture risk in later life: a lifecourse Mendelian randomisation study.
Musculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites. However, sources of bias induced by confounding factors may have distorted previous findings. Employing a lifecourse Mendelian randomisation (MR) approach by using genetic instruments to separate effects at different life stages, this investigation aims to explore how prepubertal and adult body size independently influence fracture risk in later life.Using data from a large prospective cohort, univariable and multivariable MR were conducted to simultaneously estimate the effects of age-specific genetic proxies for body size (n = 453,169) on fracture risk (n = 416,795). A two-step MR framework was additionally applied to elucidate potential mediators. Univariable and multivariable MR indicated strong evidence that higher body size in childhood reduced fracture risk (OR, 95% CI: 0.89, 0.82 to 0.96, P = 0.005 and 0.76, 0.69 to 0.85, P = 1 × 10- 6, respectively). Conversely, higher body size in adulthood increased fracture risk (OR, 95% CI: 1.08, 1.01 to 1.16, P = 0.023 and 1.26, 1.14 to 1.38, P = 2 × 10- 6, respectively). Two-step MR analyses suggested that the effect of higher body size in childhood on reduced fracture risk was mediated by its influence on higher estimated bone mineral density (eBMD) in adulthood.This investigation provides novel evidence that higher body size in childhood reduces fracture risk in later life through its influence on increased eBMD. From a public health perspective, this relationship is complex since obesity in adulthood remains a major risk factor for co-morbidities. Results additionally indicate that higher body size in adulthood is a risk factor for fractures. Protective effect estimates previously observed are likely attributed to childhood effects.
Abstract.
Author URL.
Hawkes G, Beaumont RN, Tyrrell J, Power GM, Wood A, Laakso M, Silva LF, 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. , 4(02-16).
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.
Abstract.
Author URL.
Harlow CE, Patel VV, Waterworth DM, Wood AR, Beaumont RN, Ruth KS, Tyrrell J, Oguro-Ando A, Chu AY, Frayling TM, et al (2023). Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk.
Hum Mol Genet,
32(3), 496-505.
Abstract:
Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk.
Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dl increase in Hgb levels, was not associated (at P
Abstract.
Author URL.
Hawkes G, Yengo L, Vedantam S, Marouli E, Beaumont RN, GIANT Consortium, Tyrrell J, Weedon MN, Hirschhorn J, Frayling TM, et al (2023). Identification and analysis of individuals who deviate from their genetically-predicted phenotype.
bioRxivAbstract:
Identification and analysis of individuals who deviate from their genetically-predicted phenotype.
UNLABELLED: Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol. We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL cholesterol and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions. AUTHOR SUMMARY: Human genetics is becoming increasingly useful to help predict human traits across a population owing to findings from large-scale genetic association studies and advances in the power of genetic predictors. This provides an opportunity to potentially identify individuals that deviate from genetic predictions for a common phenotype under investigation. For example, an individual may be genetically predicted to be tall, but be shorter than expected. It is potentially important to identify individuals who deviate from genetic predictions as this can facilitate further follow-up to assess likely causes. Using 158,951 unrelated individuals from the UK Biobank, with height and LDL cholesterol, as exemplar traits, we demonstrate that approximately 0.15% & 0.12% of individuals deviate from their genetically predicted phenotypes respectively. We observed these individuals to be enriched for a range of rare clinical diagnoses, as well as rare genetic factors that may be causal. Our analyses also demonstrate several methods for detecting individuals who deviate from genetic predictions that can be applied to a range of continuous human phenotypes.
Abstract.
Author URL.
Hawkes G, Yengo L, Vedantam S, Marouli E, Beaumont RN, GIANT Consortium, Tyrrell J, Weedon MN, Hirschhorn J, Frayling TM, et al (2023). Identification and analysis of individuals who deviate from their genetically-predicted phenotype.
PLoS Genet,
19(9).
Abstract:
Identification and analysis of individuals who deviate from their genetically-predicted phenotype.
Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol. We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL cholesterol and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.
Abstract.
Author URL.
O'Loughlin J, Casanova F, Fairhurst-Hunter Z, Hughes A, Bowden J, Watkins ER, Freathy RM, Millwood IY, Lin K, Chen Z, et al (2023). Mendelian randomisation study of body composition and depression in people of East Asian ancestry highlights potential setting-specific causality.
BMC Med,
21(1).
Abstract:
Mendelian randomisation study of body composition and depression in people of East Asian ancestry highlights potential setting-specific causality.
BACKGROUND: Extensive evidence links higher body mass index (BMI) to higher odds of depression in people of European ancestry. However, our understanding of the relationship across different settings and ancestries is limited. Here, we test the relationship between body composition and depression in people of East Asian ancestry. METHODS: Multiple Mendelian randomisation (MR) methods were used to test the relationship between (a) BMI and (b) waist-hip ratio (WHR) with depression. Firstly, we performed two-sample MR using genetic summary statistics from a recent genome-wide association study (GWAS) of depression (with 15,771 cases and 178,777 controls) in people of East Asian ancestry. We selected 838 single nucleotide polymorphisms (SNPs) correlated with BMI and 263 SNPs correlated with WHR as genetic instrumental variables to estimate the causal effect of BMI and WHR on depression using the inverse-variance weighted (IVW) method. We repeated these analyses stratifying by home location status: China versus UK or USA. Secondly, we performed one-sample MR in the China Kadoorie Biobank (CKB) in 100,377 participants. This allowed us to test the relationship separately in (a) males and females and (b) urban and rural dwellers. We also examined (c) the linearity of the BMI-depression relationship. RESULTS: Both MR analyses provided evidence that higher BMI was associated with lower odds of depression. For example, a genetically-instrumented 1-SD higher BMI in the CKB was associated with lower odds of depressive symptoms [OR: 0.77, 95% CI: 0.63, 0.95]. There was evidence of differences according to place of residence. Using the IVW method, higher BMI was associated with lower odds of depression in people of East Asian ancestry living in China but there was no evidence for an association in people of East Asian ancestry living in the USA or UK. Furthermore, higher genetic BMI was associated with differential effects in urban and rural dwellers within China. CONCLUSIONS: This study provides the first MR evidence for an inverse relationship between BMI and depression in people of East Asian ancestry. This contrasts with previous findings in European populations and therefore the public health response to obesity and depression is likely to need to differ based on sociocultural factors for example, ancestry and place of residence. This highlights the importance of setting-specific causality when using genetic causal inference approaches and data from diverse populations to test hypotheses. This is especially important when the relationship tested is not purely biological and may involve sociocultural factors.
Abstract.
Author URL.
Green HD, Merriel SWD, Oram RA, Ruth KS, Tyrrell J, Jones SE, Thirlwell C, Weedon MN, Bailey SER (2023). Response to: Genetic risk scores may compound rather than solve the issue of prostate cancer overdiagnosis (BJC-LT3342090).
Br J Cancer,
128(4), 487-488.
Author URL.
2022
Green H, Merriel SWD, Oram R, Ruth K, Tyrrell J, Jones S, Thirlwell C, Gillings M, Weedon M, Bailey SER, et al (2022). Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank.
Abstract:
Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank
Objectives to assess how accurately a genetic risk score (GRS) can identify incident prostate cancer in men seeing their general practitioner with lower urinary tract symptoms. Design Cohort study. Setting UK Biobank data linked to primary care records. Participants Men registered with the UK Biobank, eligible for the primary care data linkage, with a record showing that they consulted their general practitioner with lower urinary tract symptoms (LUTS) that could indicate possible undiagnosed prostate cancer. Main outcome measures a diagnosis of prostate cancer within two years of the patient’s first consultation with their general practitioner for LUTS. Results a GRS is associated with prostate cancer in men with symptoms (OR=2.54 [2.16 to 2.99] p=5e-29). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer with an AUC of 0.768 (0.739 to 0.796). Men aged 40 years and under in the bottom four GRS quintiles, aged 50 years and under in the bottom two GRS quintiles, and aged 50 to 60 years in the bottom GRS quintile had a two-year prostate cancer incidence below 1%, despite the presence of symptoms. The negative predictive value of the combined model exceeded 99%. Conclusions This study is the first to apply a genetic risk score in a clinical setting to improve the triage of men with symptoms of prostate cancer. It demonstrates the added benefit of incorporating an estimate of genetic risk of prostate cancer into the clinical assessment of symptomatic men in primary care. Assessment of prostate cancer risk in men with LUTS is currently based on presenting clinical features alone. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, with adequate safety netting, whilst those identified with the greatest risk could be fast-tracked for further investigation.
Abstract.
Oram R, Loginovic P, Ferrat L, Green H, Weedon M, Tyrrell J, Petzold A, Braithwaite T (2022). Applying a genetic risk score model to enhance prediction of future Multiple Sclerosis diagnosis at first presentation with optic neuritis: a cohort study in the UK Biobank.
Casanova F, Tyrrell J, Beaumont RN, Ji Y, Jones SE, Hattersley AT, Weedon MN, Murray A, Shore AC, Frayling TM, et al (2022). Corrigendum to: a genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio. Human Molecular Genetics, 31(9).
Zhao Y, Gardner EJ, Tuke MA, Zhang H, Pietzner M, Koprulu M, Jia RY, Ruth KS, Wood AR, Beaumont RN, et al (2022). Detection and characterization of male sex chromosome abnormalities in the UK Biobank study.
Genet Med,
24(9), 1909-1919.
Abstract:
Detection and characterization of male sex chromosome abnormalities in the UK Biobank study.
PURPOSE: the study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. METHODS: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. RESULTS: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P
Abstract.
Author URL.
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.
Abstract.
Fussey J (2022). Genetics in the diagnosis and management of thyroid cancer.
Abstract:
Genetics in the diagnosis and management of thyroid cancer
Background
Thyroid cancer is the commonest endocrine malignancy, constituting around 1% of all cancers. Medullary thyroid carcinoma (MTC) is usually sporadic, but may occur in patients with germline mutations in the rearranged during transfection (RET) gene. The sporadic form lacks germline mutations but may harbour somatic RET mutations. The risk factors for differentiated thyroid carcinoma (DTC) are not well understood, and genetic predisposition accounts for a smaller proportion of DTC than MTC.
Methods
Presenting features of patients undergoing germline RET testing were analysed in order to explore the prevalence of germline RET mutations in patients with different clinical presentations in the UK population, and a systematic review of the literature was undertaken to investigate the clinical usefulness of somatic mutations in patients with sporadic MTC. Mendelian randomisation was utilised to investigate the causal roles of several proposed modifiable risk factors for thyroid cancer.
Results
By analysing results of 1,058 patients’ germline RET analysis, I found that 8.5% of patients with presumed sporadic MTC in fact have hereditary disease. The
3
systematic review on molecular genetics in sporadic MTC highlights the emerging role of somatic mutations and epigenetic markers in prognostication in sporadic MTC. Regarding risk factors for DTC, my Mendelian randomisation studies identified a causal association between lower thyroid stimulating hormone (TSH) levels and DTC, and a possible causal relationship between type 2 diabetes mellitus (T2DM) and DTC. I was however unable to provide any evidence using genetic epidemiological techniques for a causal role for obesity, smoking, alcohol consumption or physical exercise.
Conclusions
This thesis helps to illustrate patterns of clinical presentations of patients with germline RET mutations in the United Kingdom, and reports the novel use of mendelian randomisation to investigate the role of a range of lifestyle risk factors on the risk of thyroid cancer, raising some questions about the validity of previously reported observational findings, and paving the way for further research with the vital aim of understanding the modifiable risk factors for thyroid cancer.
Abstract.
Ruth KS, Beaumont RN, Locke JM, Tyrrell J, Crandall CJ, Hawkes G, Frayling TM, Prague JK, Patel KA, Wood AR, et al (2022). Genomic insights into the mechanism of NK3R antagonists for treatment of menopausal vasomotor symptoms.
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
Abstract.
Author URL.
Borges MC, Clayton G, Freathy RM, Felix JF, Fernández-Sanlés A, Soares AG, Kilpi F, Yang Q, McEachan RRC, Richmond RC, et al (2022). Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes in up to 497,932 women.
Gormley M, Dudding T, Kachuri L, Burrows K, Chong AHW, Martin RM, Thomas SJ, Tyrrell J, Ness AR, Brennan P, et al (2022). Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.
BMC Med,
20(1).
Abstract:
Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.
BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: in univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p =
Abstract.
Author URL.
Gilchrist M, Casanova F, Tyrrell JS, Cannon S, Wood AR, Fife N, Young K, Oram RA, Weedon MN (2022). Prevalence of Fabry disease-causing variants in the UK Biobank.
Journal of Medical Genetics,
60(4), 391-396.
Abstract:
Prevalence of Fabry disease-causing variants in the UK Biobank
BackgroundFabry disease is an X-linked lysosomal storage disorder resulting from deficiency of the alpha-galactosidase a enzyme leading to accumulation of globotriaosylceramide in multiple organ sites with prominent cardiovascular and renal involvement. Global prevalence estimates of Fabry disease based on clinical ascertainment range from 1 in 40 000 to 1 in 170 000. We aimed to determine the prevalence of Fabry disease-causing variants in UK Biobank.MethodsWe soughtGLAgene variants in exome sequencing data from 200 643 individuals from UK Biobank. We used ACMG/AMP guidelines (American College of Medical Genetics/Association for Molecular Pathology) to classify pathogenicity and compared baseline biomarker data, hospital ICD-10 (International Classification of Diseases version-10) codes, general practitioner records and self-reported health data with those without pathogenic variants.ResultsWe identified 81GLAcoding variants. We identified eight likely pathogenic variants on the basis of being rare (<1/10 000 individuals) and either previously reported to cause Fabry disease, or being protein-truncating variants. Thirty-six individuals carried one of these variants. In the UK Biobank, the prevalence of likely pathogenic Fabry disease-causing variants is 1/5732 for late-onset disease-causing variants and 1/200 643 for variants causing classic Fabry disease.ConclusionFabry disease-causingGLAvariants are more prevalent in an unselected population sample than the reported prevalence of Fabry disease. These are overwhelmingly variants associated with later onset. It is possible the prevalence of later-onset Fabry disease exceeds current estimates.
Abstract.
Casanova F, O’Loughlin J, Lewis C, Frayling TM, Wood AR, Tyrrell J (2022). Simulated distributions from negative experiments highlight the importance of the body mass index distribution in explaining depression–body mass index genetic risk score interactions.
International Journal of Epidemiology,
51(5), 1581-1592.
Abstract:
Simulated distributions from negative experiments highlight the importance of the body mass index distribution in explaining depression–body mass index genetic risk score interactions
Abstract
.
. Background
. Depression and obesity are complex global health problems. Recent studies suggest that a genetic predisposition to obesity might be accentuated in people with depression, but these analyses are prone to bias. Here, we tested the hypothesis that depression accentuates genetic susceptibility to obesity and applied negative control experiments to test whether any observed interactions were real or driven by confounding and statistical biases.
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.
. Methods
. We used data from up to 378 000 Europeans in UK Biobank, a 73 variant body mass index (BMI) genetic risk score, two depression measures [depression symptoms (DS), major depression (MD)] and an antidepressant usage variable available. We tested whether (i) depression and (ii) antidepressant treatment accentuated genetic susceptibility to obesity. Finally, we performed negative control experiments by sampling individuals at random so that they had BMI distributions identical to depression cases and controls.
.
.
. Results
. Depression was associated with an accentuation of an individual’s genetic risk of obesity with evidence of interactions for both DS and MD (Pinteraction = 7 × 10–4 and 7 × 10–5 respectively). Antidepressant usage within DS cases accentuated genetic obesity risk (Pinteraction = 9 × 10–4), but not for MD (Pinteraction = 0.13). Negative control experiments suggested that the observed interactions for MD (empirical-P = 0.067) may be driven by statistical biases or confounding factors but were not possible with the larger DS groups. Antidepressant usage interaction also appears to be driven by statistical artefacts (empirical-P = 0.510 using MD and 0.162 using DS).
.
.
. Conclusion
. We have highlighted the importance of running negative experiments to confirm putative interactions in gene–environment studies. We provide some tentative evidence that depression accentuates an individual’s genetic susceptibility to higher BMI but demonstrated that the BMI distributions within cases and controls might drive these interactions.
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Abstract.
Weedon MN, Jones SE, Lane JM, Lee J, Ollila HM, Dawes A, Tyrrell J, Beaumont RN, Partonen T, Merikanto I, et al (2022). The impact of Mendelian sleep and circadian genetic variants in a population setting.
PLoS Genet,
18(9).
Abstract:
The impact of Mendelian sleep and circadian genetic variants in a population setting.
Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants in these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. No carriers for variants reported in NPSR1 or PER2 were identified. We found no association between variants analyzed and extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P = 4x10-8; and had a 57-minute earlier midpoint sleep, P = 5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.
Abstract.
Author URL.
Tyrrell J, Gillett A, Casanova F, Young K, Green H, Lewis C, Hagenaars S (2022). The impact of depression. diagnosis on diabetes and lifetime hyperglycaemia. World Congress of Psychiatric Genetic (WCPG). 13th - 17th Sep 2022.
Cresswell M, Casanova F, Beaumont RN, Wood AR, Ronan N, Hilton MP, Tyrrell J (2022). Understanding Factors That Cause Tinnitus: a Mendelian Randomization Study in the UK Biobank.
Ear Hear,
43(1), 70-80.
Abstract:
Understanding Factors That Cause Tinnitus: a Mendelian Randomization Study in the UK Biobank.
OBJECTIVES: to investigate the causal role of established risk factors and associated conditions to tinnitus and tinnitus severity in the UK Biobank. DESIGN: the prospective cohort study with large dataset of >500,000 individuals. The analytical sample of 129,731 individuals in the UK Biobank of European descent. Participants were recruited from National Health Service registries, baseline age range between 37 and 73 years, response rate to baseline survey 6%. Participants were asked subjective questions about tinnitus and its severity. Previously observed associations (n = 23) were confirmed in the UK Biobank using logistic and ordinal regression models. Two-sample Mendelian randomization approaches were then used to test causal relationships between the 23 predictors and tinnitus and tinnitus severity. The main outcome measures were observational and genetic association between key demographics and determinants and two tinnitus outcomes (current tinnitus and tinnitus severity). RESULTS: Prevalence of tinnitus was 20% and severe tinnitus 3.8%. The observational results are consistent with the previous literature, with hearing loss, older age, male gender, high BMI, higher deprivation, higher blood pressure, smoking history, as well as numerous comorbidities being associated with higher odds of current tinnitus. Mendelian randomization results showed causal correlations with tinnitus. Current tinnitus was predicted by genetically instrumented hearing loss (odds ratio [OR]: 8.65 [95% confidence interval (CI): 6.12 to 12.23]), major depression (OR: 1.26 [95% CI: 1.06 to 1.50]), neuroticism (OR: 1.48 [95% CI: 1.28 to 1.71]), and higher systolic blood pressure (OR: 1.01 [95% CI:1.00 to 1.02]). Lower odds of tinnitus were associated with longer duration in education (OR: 0.74 [95% CI: 0.63 to 0.88]), higher caffeine intake (OR: 0.89 [95% CI: 0.83 to 0.95]) and being a morning person (OR: 0.94 [95% CI: 0.90 to 0.98]). Tinnitus severity was predicted by a higher genetic liability to neuroticism (OR: 1.15 [95% CI: 1.06 to 1.26]) and schizophrenia (OR: 1.02 [95% CI: 1.00 to 1.04]). CONCLUSIONS: Tinnitus data from the UK Biobank confirm established associated factors in the literature. Genetic analysis determined causal relationships with several factors that expand the understanding of the etiology of tinnitus and can direct future pathways of clinical care and research.
Abstract.
Author URL.
Karageorgiou V, Tyrrell J, McKinley TJ, Bowden J (2022). Weak and pleiotropy robust Sex-stratified Mendelian Randomization in the one sample and two sample settings.
Author URL.
2021
Budu-Aggrey A, Watkins SH, Brumpton B, Løset M, Tyrrell J, Modalsli EH, Vie GÅ, Palmer T, Fritsche LG, Nielsen JB, et al (2021). Assessment of a causal relationship between body mass index and atopic dermatitis.
J Allergy Clin Immunol,
147(1), 400-403.
Author URL.
Fürtjes AE, Coleman JRI, Tyrrell J, Lewis CM, Hagenaars SP (2021). Associations and limited shared genetic aetiology between bipolar disorder and cardiometabolic traits in the UK Biobank.
Psychol Med,
52(16), 1-10.
Abstract:
Associations and limited shared genetic aetiology between bipolar disorder and cardiometabolic traits in the UK Biobank.
BACKGROUND: People with bipolar disorder (BPD) are more likely to die prematurely, which is partly attributed to comorbid cardiometabolic traits. Previous studies report cardiometabolic abnormalities in BPD, but their shared aetiology remains poorly understood. This study examined the phenotypic associations and shared genetic aetiology between BPD and various cardiometabolic traits. METHODS: in a subset of the UK Biobank sample (N = 61 508) we investigated phenotypic associations between BPD (ncases = 4186) and cardiometabolic traits, represented by biomarkers, anthropometric traits and cardiometabolic diseases. To determine shared genetic aetiology in European ancestry, polygenic risk scores (PRS) and genetic correlations were calculated between BPD and cardiometabolic traits. RESULTS: Several traits were significantly associated with increased risk for BPD, namely low total cholesterol, low high-density lipoprotein cholesterol, high triglycerides, high glycated haemoglobin, low systolic blood pressure, high body mass index, high waist-to-hip ratio; and stroke, coronary artery disease and type 2 diabetes diagnosis. BPD was associated with higher polygenic risk for triglycerides, waist-to-hip ratio, coronary artery disease and type 2 diabetes. Shared genetic aetiology persisted for coronary artery disease, when correcting PRS associations for cardiometabolic base phenotypes. Associations were not replicated using genetic correlations. CONCLUSIONS: This large study identified increased phenotypic cardiometabolic abnormalities in BPD participants. It is found that the comorbidity of coronary artery disease may be based on shared genetic aetiology. These results motivate hypothesis-driven research to consider individual cardiometabolic traits rather than a composite metabolic syndrome when attempting to disentangle driving mechanisms of cardiometabolic abnormalities in BPD.
Abstract.
Author URL.
van der Laan CM, Morosoli-García JJ, van de Weijer SGA, Colodro-Conde L, Ip HF, van der Laan CM, Krapohl EML, Brikell I, Sánchez-Mora C, Nolte IM, et al (2021). Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course.
Behavior Genetics,
51(5), 592-606.
Abstract:
Continuity of Genetic Risk for Aggressive Behavior Across the Life-Course
We test whether genetic influences that explain individual differences in aggression in early life also explain individual differences across the life-course. In two cohorts from the Netherlands (N = 13,471) and Australia (N = 5628), polygenic scores (PGSs) were computed based on a genome-wide meta-analysis of childhood/adolescence aggression. In a novel analytic approach, we ran a mixed effects model for each age (Netherlands: 12–70 years, Australia: 16–73 years), with observations at the focus age weighted as 1, and decaying weights for ages further away. We call this approach a ‘rolling weights’ model. In the Netherlands, the estimated effect of the PGS was relatively similar from age 12 to age 41, and decreased from age 41–70. In Australia, there was a peak in the effect of the PGS around age 40 years. These results are a first indication from a molecular genetics perspective that genetic influences on aggressive behavior that are expressed in childhood continue to play a role later in life.
Abstract.
Thompson WD, Beaumont RN, Kuang A, Warrington NM, Ji Y, Tyrrell J, Wood AR, Scholtens DM, Knight BA, Evans DM, et al (2021). Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight.
Human Molecular Genetics,
31(11), 1762-1775.
Abstract:
Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight
Abstract
.
. Background
. Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown.
.
.
. Aim
. We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI.
.
.
. Methods
. We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association.
.
.
. Results
. Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1–5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0–1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = −0.0019, P = 0.602).
.
.
. Conclusions
. Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.
.
Abstract.
Martin S, Cule M, Basty N, Tyrrell J, Beaumont RN, Wood AR, Frayling TM, Sorokin E, Whitcher B, Liu Y, et al (2021). Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease.
Diabetes,
70(8), 1843-1856.
Abstract:
Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease.
To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants: one with "adverse" metabolic effects (UFA) and the other with, paradoxically, "favorable" metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, and higher fat in subcutaneous and visceral adipose tissue, liver, and pancreas for UFA and a favorable metabolic profile, lower risk of disease, higher CRP and higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for a risk-increasing effect of UFA and protective effect of FA for type 2 diabetes, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting, and treating cardiometabolic diseases.
Abstract.
Author URL.
Green HD, Thomas NJ, Tyrrell J, Jones A, Evans JP, Smith C, Oram RA, Jones AG, Weedon MN (2021). Genetic analysis confirms type 1 diabetes is a cause of multiple musculoskeletal conditions.
Author URL.
Ruth K, Beaumont RN, Frayling TM, Joaquim MDR, Shekari S, Tyrrell J, Wood AR, Murray A (2021). Genetic insights into biological mechanisms governing human ovarian ageing.
NatureAbstract:
Genetic insights into biological mechanisms governing human ovarian ageing
Reproductive longevity is critical for fertility and impacts healthy ageing in women1,2, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ~200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Abstract.
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
Abstract.
Author URL.
Heald AH, Martin S, Fachim H, Green HD, Young KG, Malipatil N, Siddals K, Cortes G, Tyrrell J, Wood AR, et al (2021). Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile.
Diabetic Medicine,
38(9).
Abstract:
Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile
AbstractAimsChange in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression.MethodsWe involved people with type 2 diabetes from two UK‐based cohorts: 11,914 individuals with GP follow‐up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross‐sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow‐up time points with 1‐year intervals.ResultsThe ‘favourable adiposity’ genetic score was cross‐sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high‐density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (−0.04 mmol/L [−0.07, −0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow‐up.There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid‐lowering (0.91 [0.86, 0.97]) and anti‐hypertensive medication (0.95 [0.91, 0.99]).ConclusionsIn individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long‐term and having lower odds of requiring lipid‐lowering or anti‐hypertensive medication in spite of relatively higher adiposity.
Abstract.
Casanova F, O'Loughlin J, Martin S, Beaumont RN, Wood AR, Watkins ER, Freathy RM, Hagenaars SP, Frayling TM, Yaghootkar H, et al (2021). Higher adiposity and mental health: causal inference using Mendelian randomization.
Hum Mol Genet,
30(24), 2371-2382.
Abstract:
Higher adiposity and mental health: causal inference using Mendelian randomization.
Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one- and two- sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß: -0.15, 95%CI: -0.26, -0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being.
Abstract.
Author URL.
Anderson EL, Richmond RC, Jones SE, Hemani G, Wade KH, Dashti HS, Lane JM, Wang H, Saxena R, Brumpton B, et al (2021). Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.
Int J Epidemiol,
50(3), 817-828.
Abstract:
Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.
BACKGROUND: it is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD. METHODS: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk. RESULTS: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated. CONCLUSIONS: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.
Abstract.
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.
Abstract.
Author URL.
Giannakopoulou O, Lin K, Meng X, Su M-H, Kuo P-H, Peterson RE, Awasthi S, Moscati A, Coleman JRI, Bass N, et al (2021). The Genetic Architecture of Depression in Individuals of East Asian Ancestry: a Genome-Wide Association Study.
JAMA Psychiatry,
78(11), 1258-1269.
Abstract:
The Genetic Architecture of Depression in Individuals of East Asian Ancestry: a Genome-Wide Association Study.
IMPORTANCE: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. OBJECTIVE: to investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. EXPOSURES: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. MAIN OUTCOMES AND MEASURES: Depression status was defined based on health records and self-report questionnaires. RESULTS: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent. CONCLUSIONS AND RELEVANCE: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.
Abstract.
Author URL.
O'Loughlin J, Casanova F, Jones SE, Hagenaars SP, Beaumont RN, Freathy RM, Watkins ER, Vetter C, Rutter MK, Cain SW, et al (2021). Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.
Mol Psychiatry,
26(11), 6305-6316.
Abstract:
Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.
Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings.
Abstract.
Author URL.
Gormley M, Yarmolinsky J, Dudding T, Burrows K, Martin RM, Thomas S, Tyrrell J, Brennan P, Pring M, Boccia S, et al (2021). Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: a Mendelian randomization study.
PLoS Genet,
17(4).
Abstract:
Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: a Mendelian randomization study.
Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.
Abstract.
Author URL.
2020
RUTH KS, DAY F, TYRRELL J, MURRAY A, ONG K, FRAYLING T, PERRY J (2020). 1907-P: Using Human Genetics to Test the Disease Consequences of Varying Testosterone Levels in Men and Women. Diabetes, 69(Supplement_1).
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.
Abstract.
Author URL.
Gormley M, Dudding T, Sanderson E, Martin RM, Thomas S, Tyrrell J, Ness AR, Brennan P, Munafò M, Pring M, et al (2020). A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer.
Nature Communications,
11(1).
Abstract:
A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer
The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.
Abstract.
Lin S, Green HD, Hendy P, Heerasing NM, Chanchlani N, Hamilton B, Walker GJ, Heap GA, Hobart J, Martin RJ, et al (2020). Clinical Features and Genetic Risk of Demyelination Following Anti-TNF Treatment.
J Crohns Colitis,
14(12), 1653-1661.
Abstract:
Clinical Features and Genetic Risk of Demyelination Following Anti-TNF Treatment.
BACKGROUND: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. METHODS: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. RESULTS: Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7-63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median time of 6.8 months [0.1-28.7]. After 33.0 months of follow-up, partial recovery was observed in 29 [55%] patients, relapsing and remitting episodes in nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10-4, standard deviation [SD] 0.0039) and controls [mean -1.1 × 10-3, SD 0.0042] [p = 0.23]. CONCLUSIONS: Patients who experienced demyelination events following anti-TNF exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
Abstract.
Author URL.
Fussey JM, Beaumont RN, Wood AR, Vaidya B, Smith J, Tyrrell J (2020). Does Obesity Cause Thyroid Cancer? a Mendelian Randomization Study.
J Clin Endocrinol Metab,
105(7), e2398-e2407.
Abstract:
Does Obesity Cause Thyroid Cancer? a Mendelian Randomization Study.
BACKGROUND: the incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. METHODS: We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. RESULTS: Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). CONCLUSIONS: Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.
Abstract.
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.
Sukcharoen K, Sharp SA, Thomas NJ, Kimmitt RA, Harrison J, Bingham C, Mozere M, Weedon MN, Tyrrell J, Barratt J, et al (2020). IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank.
Kidney International Reports,
5(10), 1643-1650.
Abstract:
IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank
Background: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). Methods: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. Results: the IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23–4.38) than in controls (3.98; 3.97–3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02–4.06) than UKBB controls (3.98; 3.97–3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02–4.13) versus (3.98; 3.97–3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. Conclusions: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts.
Abstract.
Harrison S, Davies AR, Dickson M, Tyrrell J, Green MJ, Katikireddi SV, Campbell D, Munafò M, Dixon P, Jones HE, et al (2020). The causal effects of health conditions and risk factors on social and socioeconomic outcomes: Mendelian randomization in UK Biobank.
Int J Epidemiol,
49(5), 1661-1681.
Abstract:
The causal effects of health conditions and risk factors on social and socioeconomic outcomes: Mendelian randomization in UK Biobank.
BACKGROUND: We aimed to estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy makers and decision makers allocate resources efficiently and effectively. METHODS: We used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, type 2 diabetes) and five health risk factors [alcohol intake, body mass index (BMI), cholesterol, systolic blood pressure, smoking] on 19 social and socioeconomic outcomes in 336 997 men and women of White British ancestry in UK Biobank, aged between 39 and 72 years. Outcomes included annual household income, employment, deprivation [measured by the Townsend deprivation index (TDI)], degree-level education, happiness, loneliness and 13 other social and socioeconomic outcomes. RESULTS: Results suggested that BMI, smoking and alcohol intake affect many socioeconomic outcomes. For example, smoking was estimated to reduce household income [mean difference = -£22 838, 95% confidence interval (CI): -£31 354 to -£14 321] and the chance of owning accommodation [absolute percentage change (APC) = -20.8%, 95% CI: -28.2% to -13.4%], of being satisfied with health (APC = -35.4%, 95% CI: -51.2% to -19.5%) and of obtaining a university degree (APC = -65.9%, 95% CI: -81.4% to -50.4%), while also increasing deprivation (mean difference in TDI = 1.73, 95% CI: 1.02 to 2.44, approximately 216% of a decile of TDI). There was evidence that asthma decreased household income, the chance of obtaining a university degree and the chance of cohabiting, and migraine reduced the chance of having a weekly leisure or social activity, especially in men. For other associations, estimates were null. CONCLUSIONS: Higher BMI, alcohol intake and smoking were all estimated to adversely affect multiple social and socioeconomic outcomes. Effects were not detected between health conditions and socioeconomic outcomes using Mendelian randomization, with the exceptions of depression, asthma and migraines. This may reflect true null associations, selection bias given the relative health and age of participants in UK Biobank, and/or lack of power to detect effects.
Abstract.
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.
2019
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.
Abstract.
Author URL.
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.
Thompson WD, Tyrrell J, Borges MC, Beaumont RN, Knight BA, Wood AR, Ring SM, Hattersley AT, Freathy RM, Lawlor DA, et al (2019). Association of maternal circulating 25(OH)D and calcium with birth weight: a mendelian randomisation analysis. PLoS Medicine, 16
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.
Abstract.
Tyrrell J, Mulugeta A, Wood A, Zhou A, Beaumont R, Tuke M, Jones S, Ruth K, Yaghootkar H, Lewis C, et al (2019). DOES HIGH BMI IN THE ABSENCE OF METABOLIC CONSEQUENCES CAUSE DEPRESSION?.
Author URL.
Duckworth A, Gibbons MA, Wood AR, Lunnon K, Lindsay MA, Tyrrell J, Scotton CJ (2019). EVIDENCE THAT TELOMERE LENGTH IS CAUSAL FOR IDIOPATHIC PULMONARY FIBROSIS BUT NOT CHRONIC OBSTRUCTIVE PULMONARY DISEASE: a UK BIOBANK MENDELIAN RANDOMISATION STUDY.
Author URL.
Harrison S, Davies AR, Dickson M, Tyrrell J, Green MJ, Katikireddi SV, Campbell D, Munafo M, Dixon P, Jones HE, et al (2019). Estimated effects of health conditions and risk factors on social and socioeconomic outcomes: mendelian randomisation of UK Biobank data.
Author URL.
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
Wangs H, Lane J, Jones S, Dashti H, Ollila H, Wood A, van Hees V, Brumpton B, Winsvold B, Kantoj K, et al (2019). GENOME-WIDE ASSOCIATION ANALYSIS OF SELF-REPORTED DAYTIME SLEEPINESS IDENTIFIES 42 LOCI THAT SUGGEST BIOLOGICAL SUBTYPES.
Author URL.
Bovijn J, Jackson L, Censin J, Chen CY, Laisk T, Laber S, Ferreira T, Pulit SL, Glastonbury CA, Smoller JW, et al (2019). GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.
American Journal of Human Genetics,
104(1), 157-163.
Abstract:
GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology
Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10−14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.
Abstract.
Ruth KS, Beaumont RN, Tyrrell J, Wood AR, Jones SE, Weedon MN, Frayling TM, Murray A (2019). Genetic signals for use of hormone replacement therapy in post-menopausal women suggest potential drug targets and reflect changes in health practice.
Author URL.
Green HD, Beaumont RN, Thomas A, Hamilton B, Wood AR, Sharp S, Jones SE, Tyrrell J, Walker G, Goodhand J, et al (2019). Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.
J Crohns Colitis,
13(12), 1578-1582.
Abstract:
Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.
BACKGROUND AND AIMS: the causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank. METHODS: in total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores. RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis. CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.
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Author URL.
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.
Abstract.
Author URL.
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.
Abstract.
Schafmayer C, Harrison JW, Buch S, Lange C, Reichert MC, Hofer P, Cossais F, Kupcinskas J, von Schönfels W, Schniewind B, et al (2019). Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
Gut,
68(5), 854-865.
Abstract:
Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p
Abstract.
Author URL.
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.
Abstract.
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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Author URL.
Tyrrell J, Paterson C, Curnow A (2019). Insights gained from regression analysis of PpIX fluorescence imaging undertaken during routine dermatological photodynamic therapy.
Abstract:
Insights gained from regression analysis of PpIX fluorescence imaging undertaken during routine dermatological photodynamic therapy
Abstract.
Green H, Beaumont R, Jones S, Yaghootkar H, Wood A, Goodhand J, Kennedy N, Ahmad T, Frayling T, Weedon M, et al (2019). MODIFIABLE RISK FACTORS FOR GASTRO-OESOPHAGAL REFLUX DISEASE: a MENDELIAN RANDOMISATION STUDY.
Author URL.
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.
Abstract.
Author URL.
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.
Abstract.
Author URL.
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.
Abstract.
Author URL.
Tyrrell J, Paterson C, Curnow A (2019). Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Cancers (Basel),
11(1).
Abstract:
Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of dermatological cancers and precancers. Improvement of efficacy is required to widen its application. Clinical protoporphyrin IX (PpIX) fluorescence data were obtained using a pre-validated, non-invasive imaging system during routine methyl aminolevulinate (MAL)-PDT treatment of 172 patients with licensed dermatological indications (37.2% actinic keratosis, 27.3% superficial basal cell carcinoma and 35.5% Bowen's disease). Linear and logistic regressions were employed to model any relationships between variables that may have affected PpIX accumulation and/or PpIX photobleaching during irradiation and thus clinical outcome at three months. Patient age was found to be associated with lower PpIX accumulation/photobleaching, however only a reduction in PpIX photobleaching appeared to consistently adversely affect treatment efficacy. Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower PpIX accumulation and subsequent photobleaching adversely affecting the outcome achieved. If air cooling pain relief was employed during light irradiation, PpIX photobleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance. PpIX photobleaching during the first treatment was concluded to be an excellent predictor of clinical outcome across all lesion types.
Abstract.
Author URL.
Curnow A, Tyrrell J, Paterson C (2019). Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Abstract:
Regression Analysis of Protoporphyrin IX Measurements Obtained During Dermatological Photodynamic Therapy.
Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of dermatological cancers and precancers. Improvement of efficacy is required to widen its application. Clinical protoporphyrin IX (PpIX) fluorescence data were obtained using a pre-validated, non-invasive imaging system during routine methyl aminolevulinate (MAL)-PDT treatment of 172 patients with licensed dermatological indications (37.2% actinic keratosis, 27.3% superficial basal cell carcinoma and 35.5% Bowen’s disease). Linear and logistic regressions were employed to model any relationships between variables that may have affected PpIX accumulation and/or PpIX photobleaching during irradiation and thus clinical outcome at three months. Patient age was found to be associated with lower PpIX accumulation/photobleaching, however only a reduction in PpIX photobleaching appeared to consistently adversely affect treatment efficacy. Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower PpIX accumulation and subsequent photobleaching adversely affecting the outcome achieved. If air cooling pain relief was employed during light irradiation, PpIX photobleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance. PpIX photobleaching during the first treatment was concluded to be an excellent predictor of clinical outcome across all lesion types.
Abstract.
Tuke MA, Ruth KS, Wood AR, Beaumont RN, Tyrrell J, Jones SE, Yaghootkar H, Turner CLS, Donohoe ME, Brooke AM, et al (2019). Response to Prakash et al.
Genet Med,
21(8), 1884-1885.
Author URL.
Middeldorp CM, Felix JF, Mahajan A, McCarthy MI (2019). The early growth genetics (Egg) and early genetics and lifecourse epidemiology (eagle) consortia: Design, results and future prospects.
European Journal of Epidemiology,
34(3), 279-300.
Abstract:
The early growth genetics (Egg) and early genetics and lifecourse epidemiology (eagle) consortia: Design, results and future prospects
The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been suc-cessfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in com-bination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Abstract.
Wright CF, Tuke MA, West B, Jones S, Patel K, Laver TW, Beaumont RN, Tyrrell J, Wood AR, Murray A, et al (2019). Using UK Biobank to assess the pathogenicity, penetrance and expressivity of monogenic disease variants.
Author URL.
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
Abstract.
Author URL.
2018
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.
Tyrrell J, Yaghootkar H, Jones SE, Beaumont R, Wood AR, Tuke MA, Ruth KS, Andrews RC, Frayling TM (2018). Broad changes in body mass index between age 10 and adulthood are associated with type 2 diabetes risk independently of adult body mass index.
Author URL.
Yaghootkar H, Ji Y, Yiorkas AM, Tyrrell J, Jones SE, Beaumont R, Wood AR, Blakemore AIF, Bell JD, Frayling TM, et al (2018). Carrying more 'favourable adiposity' genetic factors is associated with higher adiposity but lower ectopic fat and lower risk of Type 2 diabetes.
Author URL.
Yaghootkar H, Ji Y, Yiorkas AM, Frau F, Mook-Kanamori D, De Mutsert R, Tyrrell J, Jones SE, Beaumont R, Wood AR, et al (2018). Genome-Wide and Abdominal Imaging Data Characterizes Common Alleles Associated with Higher BMI and Subcutaneous Fat but Less Liver Fat and Lower Risk of Type 2 Diabetes.
Author URL.
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.
Beaumont RN, Warrington NM, Horikoshi M, Day FR, Ong KK, McCarthy MI, Perry JRB, Freathy RM, Evans DM, EGG EGG, et al (2018). Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic disease.
Author URL.
Wood AR, Jones SE, Richmond R, Ahmad S, Yaghootkar H, Beaumont R, Ruth KS, Tuke M, Murray A, Freathy RM, et al (2018). Physical Inactivity and Sleep Inefficiency Accentuate the Genetic Risk of Obesity.
Author URL.
Yeo NL, White MP, Ronan N, Whinney DJ, Curnow A, Tyrrell J (2018). Stress and Unusual Events Exacerbate Symptoms in Menière's Disease: a Longitudinal Study.
Otol Neurotol,
39(1), 73-81.
Abstract:
Stress and Unusual Events Exacerbate Symptoms in Menière's Disease: a Longitudinal Study.
HYPOTHESIS: Stress and unusual events are associated with a higher likelihood of attacks and increased symptom severity in Menière's disease (MD). BACKGROUND: MD is an unpredictable condition which severely impacts the quality of life of those affected. It is thought that unusual activity and stress may act as an attack trigger in MD, but research in this area has been limited to date. METHODS: This was a longitudinal study conducted over two phases. A mobile phone application was used to collect daily data on Menière's attacks and individual symptoms (aural fullness, dizziness, hearing loss, and tinnitus), as well as prevalence of unusual events (phase I), and stress levels (phase II). There were 1,031 participants (730 women, mean age 46.0 yr) in phase I and 695 participants (484 women, mean age 47.7 yr) in phase II. Panel data regression analyses were employed to examine for associations between unusual events/stress and attacks/symptoms, including the study of 24 hours lead and lag effects. RESULTS: Unusual events and higher stress levels were associated with higher odds of Menière's attacks and more severe symptoms. The odds of experiencing an attack were 2.94 (95% confidence interval [CI] 2.37, 3.65) with reporting of unusual events and increased by 1.24 (95% CI 1.20, 1.28) per unit increase in stress level. Twenty-four hour lead (OR 1.10 [95% CI 1.07, 1.14]) and lag (OR 1.10 [95% CI 1.06, 1.13]) effects on attacks were also found with increases in stress. CONCLUSION: This study provides the strongest evidence to date that stress and unusual events are associated with attacks and symptom exacerbation in MD. Improving our understanding of stress and unusual events as triggers in Menière's may reduce the uncertainty associated with this condition and lead to improved quality of life for affected individuals.
Abstract.
Author URL.
2017
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.
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.
Justice AE, Winkler TW, Feitosa MF, Graff M, Fisher VA, Young K, Barata L, Deng X, Czajkowski J, Hadley D, et al (2017). Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.
Nat Commun,
8Abstract:
Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
Abstract.
Author URL.
Yaghootkar H, Ji Y, Tyrrell J, Jones SE, Beaumont R, Tuke MA, Ruth KS, Freathy RM, Wood AR, Murray A, et al (2017). Identification of alleles associated with higher body fat percentage but lower risk of type 2 diabetes.
Author URL.
Curnow A, Buxton C, Tyrrell J (2017). Mechanistic insights gained through regression analysis of PpIX accumulation and photobleaching during dermatological MAL-PDT. Photodiagnosis and Photodynamic Therapy, 17
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.
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.
Schmidt W, Sarran C, Ronan N, Barrett G, Whinney DJ, Fleming LE, Osborne NJ, Tyrrell J (2017). The Weather and Ménière's Disease: a Longitudinal Analysis in the UK.
Otol Neurotol,
38(2), 225-233.
Abstract:
The Weather and Ménière's Disease: a Longitudinal Analysis in the UK.
HYPOTHESIS: Changes in the weather influence symptom severity in Ménière's disease (MD). BACKGROUND: MD is an unpredictable condition that significantly impacts on quality of life. It is suggested that fluctuations in the weather, especially atmospheric pressure may influence the symptoms of MD. However, to date, limited research has investigated the impact of the weather on MD. METHODS: in a longitudinal study, a mobile phone application collected data from 397 individuals (277 females and 120 males with an average age of 50 yr) from the UK reporting consultant-diagnosed MD. Daily symptoms (vertigo, aural fullness, tinnitus, hearing loss, and attack prevalence) and GPS locations were collected; these data were linked with Met Office weather data (including atmospheric pressure, humidity, temperature, visibility, and wind speed). RESULTS: Symptom severity and attack prevalence were reduced on days when atmospheric pressure was higher. When atmospheric pressure was below 1,013 hectopascals, the risk of an attack was 1.30 (95% confidence interval: 1.10, 1.54); when the humidity was above 90%, the risk of an attack was 1.26 (95% confidence interval 1.06, 1.49). CONCLUSION: This study provides the strongest evidence to date that changes in atmospheric pressure and humidity are associated with symptom exacerbation in MD. Improving our understanding of the role of weather and other environmental triggers in Ménière's may reduce the uncertainty associated with living with this condition, significantly contributing to improved quality of life.
Abstract.
Author URL.
2016
Bell SL, Tyrrell J, Phoenix C (2016). A day in the life of a Ménière’s patient: understanding the lived experiences and mental health impacts of Ménière’s disease. Sociology of Health and Illness
Frayling TM, Tyrrell J (2016). Authors' reply to Toth.
BMJ,
353 Author URL.
Tyrrell J, Yaghootkar H, Beaumont R, Jones SE, Ames RM, Tuke MA, Ruth KS, Kutalik Z, Freathy RM, Murray A, et al (2016). Gene-obesogenic environment interactions in the UK Biobank study.
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.
Yaghootkar H, Lotta L, Tyrrell J, Smit R, Jones S, Donnelly L, Beaumont R, Campbell A, Tuke M, Hayward C, et al (2016). Genetic Evidence for a Link between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.
Author URL.
Jones SE, Tyrrell J, Wood AR, Beaumont R, Ruth K, Tuke M, Yaghootkar H, Teder-Laving M, Hayward C, Roenneberg T, et al (2016). Genetic Studies of Sleep and Morningness and Their Relationship with Obesity and Type 2 Diabetes.
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
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
Tyrrell J, Yaghootkar H, Beaumont R, Jones SE, Ames R, Tuke MA, Ruth KS, Kutalik Z, Freathy RM, Murray A, et al (2016). High Risk Obesogenic Environments Accentuate Genetic Susceptibility to Obesity.
Author URL.
Tyrrell J, Jones SE, Beaumont R, Astley C, Lovell R, Yaghootkar H, Tuke M, Ruth KS, Freathy RM, Hirschhorn JN, et al (2016). Higher BMI Leads to Lower Socioeconomic Status: a Mendelian Randomisation Study in the UK Biobank.
Author URL.
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.
Bell SL, Tyrrell J, Phoenix C (2016). Ménière’s disease and biographical disruption: where family transitions collide. Social Science and Medicine
Tyrrell J, Schmidt W, Williams DH, Redshaw CH (2016). Physical activity in ankylosing spondylitis: evaluation and analysis of an eHealth tool. Journal of Innovation in Health Informatics
Yaghootkar H, Bancks MP, Jones SE, McDaid AF, Beaumont R, Donnelly L, Wood AR, Campbell A, Tyrrell J, Hocking LJ, et al (2016). Quantifying the Extent to Which Index Event Biases Influence Large Genetic Association Studies.
Author URL.
Tyrrell J, Whinney DJ, Taylor T (2016). The Cost of Ménière's Disease: a Novel Multisource Approach.
Ear Hear,
37(3), e202-e209.
Abstract:
The Cost of Ménière's Disease: a Novel Multisource Approach.
OBJECTIVES: to estimate the annual cost of Ménière's disease and the cost per person in the UK population and to investigate the direct and indirect costs of the condition. DESIGN: the authors utilized a multidata approach to provide the first estimate of the cost of Ménière's. Data from the UK Biobank (a study of 500,000 individuals collected between 2007 and 2012), the Hospital Episode Statistics (data on all hospital admissions in England from 2008 to 2012) and the UK Ménière's Society (2014) were used to estimate the cost of Ménière's. Cases were self-reported in the UK Biobank and UK Ménière's Society, within the Hospital Episode Statistics cases were clinician diagnosed. The authors estimated the direct and indirect costs of the condition, using count data to represent numbers of individuals reporting specific treatments, operations etc. and basic statistical analyses (χ tests, linear and logistic regression) to compare cases and controls in the UK Biobank. RESULTS: Ménière's was estimated to cost between £541.30 million and £608.70 million annually (equivalent to US $829.9 to $934.2 million), equating to £3,341 to £3,757 ($5112 to $5748) per person per annum. The indirect costs were substantial, with loss of earnings contributing to over £400 million per annum. CONCLUSIONS: for the first time, the authors were able to estimate the economic burden of Ménière's disease. In the UK, the annual cost of this condition is substantial. Further research is required to develop cost-effective treatments and management strategies for Ménière's to reduce the economic burden of the disease. These findings should be interpreted with caution due to the uncertainties inherent in the analysis.
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.
2015
Osborne NJ, Amos B, Tyrrell J (2015). Adult Drug and Food Allergy in the UK Biobank Cohort Study.
Author URL.
Tyrrell JS, Taylor MS, Whinney D, Osborne NJ (2015). Associations of Leg Length, Trunk Length, and Total Adult Height with Ménière's: Cross-Sectional Analysis in the UK Biobank.
Ear Hear,
36(3), e122-e128.
Abstract:
Associations of Leg Length, Trunk Length, and Total Adult Height with Ménière's: Cross-Sectional Analysis in the UK Biobank.
OBJECTIVES: to investigate whether adverse intrauterine and/or childhood exposures, using established anthropometric measures (e.g. components of adult height, including total height, leg length, and trunk length) as a proxy for childhood exposures, are associated with self-reported Ménière's disease. DESIGN: Cross-sectional data from the UK Biobank were used to compare 1,327 self-reported Ménière's cases with 479,500 controls. The authors used logistic regression models to investigate the relation of Ménière's disease with the components of adult height. Models were adjusted for a range of potential confounders including age, sex, body mass index, ethnicity, type 2 diabetes, coronary heart disease, and socioeconomic status. RESULTS: in the UK Biobank, Ménière's was inversely associated with overall stature (odds ratio [OR] per standard deviation increase in height, 0.87; 95% confidence interval [CI], 0.80-0.94) and leg length (OR, 0.88; 95% CI, 0.82-0.94) in fully adjusted models. No association was noted in adjusted models with trunk length (OR, 0.94; 95% CI, 0.88-1.01). CONCLUSIONS: the specific association between leg length, a potential marker of adverse childhood environments, and Ménière's may suggest that early-life environmental exposures that influence skeletal growth may also influence the risk of developing Ménière's in later life.
Abstract.
Author URL.
Tyrrell JS, Taylor MS, Whinney D, Osborne NJ (2015). Associations of Leg Length, Trunk Length, and Total Adult Height with Menière's: Cross-Sectional Analysis in the UK Biobank.
Ear and Hearing,
36(3), e122-e128.
Abstract:
Associations of Leg Length, Trunk Length, and Total Adult Height with Menière's: Cross-Sectional Analysis in the UK Biobank
To investigate whether adverse intrauterine and/or childhood exposures, using established anthropometric measures (e.g. components of adult height, including total height, leg length, and trunk length) as a proxy for childhood exposures, are associated with selfreported Ménière's disease. Design: Cross-sectional data from the UK Biobank were used to compare 1,327 self-reported Ménière's cases with 479,500 controls. The authors used logistic regression models to investigate the relation of Ménière's disease with the components of adult height. Models were adjusted for a range of potential confounders including age, sex, body mass index, ethnicity, type 2 diabetes, coronary heart disease, and socioeconomic status. Results: in the UK Biobank, Ménière's was inversely associated with overall stature (odds ratio [OR] per standard deviation increase in height, 0.87; 95% confidence interval [CI], 0.80-0.94) and leg length (OR, 0.88; 95% CI, 0.82-0.94) in fully adjusted models. No association was noted in adjusted models with trunk length (OR, 0.94; 95% CI, 0.88-1.01). Conclusions: the specific association between leg length, a potential marker of adverse childhood environments, and Ménière's may suggest that early-life environmental exposures that influence skeletal growth may also influence the risk of developing Ménière's in later life.
Abstract.
Morris RW, Taylor AE, Fluharty ME, Bjørngaard JH, Åsvold BO, Elvestad Gabrielsen M, Campbell A, Marioni R, Kumari M, Korhonen T, et al (2015). Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.
BMJ Open,
5(8).
Abstract:
Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.
OBJECTIVES: to investigate, using a Mendelian randomisation approach, whether heavier smoking is associated with a range of regional adiposity phenotypes, in particular those related to abdominal adiposity. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene region) as a proxy for smoking heaviness, of the associations of smoking heaviness with a range of adiposity phenotypes. PARTICIPANTS: 148,731 current, former and never-smokers of European ancestry aged ≥ 16 years from 29 studies in the consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Waist and hip circumferences, and waist-hip ratio. RESULTS: the data included up to 66,809 never-smokers, 43,009 former smokers and 38,913 current daily cigarette smokers. Among current smokers, for each extra minor allele, the geometric mean was lower for waist circumference by -0.40% (95% CI -0.57% to -0.22%), with effects on hip circumference, waist-hip ratio and body mass index (BMI) being -0.31% (95% CI -0.42% to -0.19), -0.08% (-0.19% to 0.03%) and -0.74% (-0.96% to -0.51%), respectively. In contrast, among never-smokers, these effects were higher by 0.23% (0.09% to 0.36%), 0.17% (0.08% to 0.26%), 0.07% (-0.01% to 0.15%) and 0.35% (0.18% to 0.52%), respectively. When adjusting the three central adiposity measures for BMI, the effects among current smokers changed direction and were higher by 0.14% (0.05% to 0.22%) for waist circumference, 0.02% (-0.05% to 0.08%) for hip circumference and 0.10% (0.02% to 0.19%) for waist-hip ratio, for each extra minor allele. CONCLUSIONS: for a given BMI, a gene variant associated with increased cigarette consumption was associated with increased waist circumference. Smoking in an effort to control weight may lead to accumulation of central adiposity.
Abstract.
Author URL.
Tyrrell J, White M, Barrett G, Ronan N, Phoenix C, Whinney D, Osborne N (2015). Mental Health and Subjective Wellbeing of individuals with Ménière’s: Cross Sectional Analysis in the UK Biobank. Otology & Neurotology
Kendall M, Hodges NJ, Whitwell H, Tyrrell J, Cangul H (2015). Nanoparticle growth and surface chemistry changes in cell-conditioned culture medium.
Philos Trans R Soc Lond B Biol Sci,
370(1661).
Abstract:
Nanoparticle growth and surface chemistry changes in cell-conditioned culture medium.
When biomolecules attach to engineered nanoparticle (ENP) surfaces, they confer the particles with a new biological identity. Physical format may also radically alter, changing ENP stability and agglomeration state within seconds. In order to measure which biomolecules are associated with early ENP growth, we studied ENPs in conditioned medium from A549 cell culture, using dynamic light scattering (DLS) and linear trap quadrupole electron transfer dissociation mass spectrometry. Two types of 100 nm polystyrene particles (one uncoated and one with an amine functionalized surface) were used to measure the influence of surface type. In identically prepared conditioned medium, agglomeration was visible in all samples after 1 h, but was variable, indicating inter-sample variability in secretion rates and extracellular medium conditions. In samples conditioned for 1 h or more, ENP agglomeration rates varied significantly. Agglomerate size measured by DLS was well correlated with surface sequestered peptide number for uncoated but not for amine coated polystyrene ENPs. Amine-coated ENPs grew much faster and into larger agglomerates associated with fewer sequestered peptides, but including significant sequestered lactose dehydrogenase. We conclude that interference with extracellular peptide balance and oxidoreductase activity via sequestration is worthy of further study, as increased oxidative stress via this new mechanism may be important for cell toxicity.
Abstract.
Author URL.
Curnow A, Tyrrell J (2015). The mechanism of action of topical dermatological photodynamic therapy. In (Ed)
Photodynamic Therapy: Fundamentals, Applications and Health Outcomes, 59-102.
Abstract:
The mechanism of action of topical dermatological photodynamic therapy
Abstract.
Sharpe RA, Thornton CR, Tyrell J, Nikolaou V, Osborne NJ (2015). Variable risk of atopic disease due to indoor fungal exposure in NHANES 2005-2006. Clinical and Experimental Allergy, 45(10), 1566-1578.
2014
Freathy RM, Tyrrell J, Bradfield JP, Cavadino A, Feenstra B, Hayes MG, Hottenga JJ, Huikari V, Kreiner-Moller E, Metrustry S, et al (2014). Genetic analyses identify positive causal effects of maternal fasting glucose, Type 2 diabetes and vitamin D levels, and an inverse causal effect of maternal blood pressure, on offspring birth weight.
DIABETIC MEDICINE,
31, 18-18.
Author URL.
Tyrrell JS, Whinney DJD, Ukoumunne OC, Fleming LE, Osborne NJ (2014). Prevalence, associated factors, and comorbid conditions for Ménière's disease.
Ear Hear,
35(4), e162-e169.
Abstract:
Prevalence, associated factors, and comorbid conditions for Ménière's disease.
OBJECTIVES: the aims of this study were to estimate the prevalence of Ménière's disease and investigate its relationship with: demographic factors; symptoms and conditions that are known or hypothesized to be associated with Ménière's disease; other physical diseases; mental health. DESIGN: the authors used cross-sectional data from the UK Biobank to compare 1376 self-reported Ménière's participants with over 500,000 without Ménière's. The data set has comprehensive anthropometric measures, questionnaire data investigating health, well-being, diet, and medical and drug-prescribing history for each participant. The authors used logistic regression models to investigate the relationship of Ménière's disease with: demographic factors; symptoms and conditions that are known or hypothesized to be associated with Ménière's disease; other physical diseases; and mental health. RESULTS: Ménière's disease was more common in participants who were older (adjusted odds ratio per 10-year increase: 1.5 [95% confidence interval:1.4-1.6]), white (odds ratio: 1.7;1.2-2.3), female (1.4;1.3-1.6), and having higher body mass index categories (p < 0.001). The Ménière's group had greater odds of hearing difficulty (10.9;9.6-12.5), current tinnitus (68.3;47.8-97.5), and had fallen more than once in the last year (2.1;1.8-2.5). Ménière's participants had greater odds of reporting at least one disease from each grouping of allergic, immune dysfunction, or autonomic dysfunction (2.2;1.8-2.6), and poor mental health (2.1;1.8-2.5). CONCLUSIONS: This study provides an evidence base that improves understanding of Ménière's disease. Associations were noted with a number of diseases, and the authors hypothesize a role for the autonomic nervous system and immune system dysfunction in Ménière's etiology. The study also highlights the physical and mental health correlates of the condition.
Abstract.
Author URL.
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.
2013
Shiue I, Boyle RJ, Tyrrell J, Ukoumunne O, Osborne NJ (2013). Abnormal liver function is associated with food sensitisation: NHANES, 20052006.
Author URL.
Depledge MH, Tyrrell J, Fleming LE, Holgate ST (2013). Are marine environmental pollutants influencing global patterns of human disease?.
Mar Environ Res,
83, 93-95.
Abstract:
Are marine environmental pollutants influencing global patterns of human disease?
Thousands of toxic chemicals, many of which pollute marine ecosystems, potentially cause diseases, but building a consensus view of the significance of human body burdens of environmental chemicals is proving difficult. Causative mechanisms are often lacking. Older members of the population, of which there are increasing numbers worldwide, accumulate higher body burdens than the young, and may be especially at risk. It also remains unclear when crucially sensitive periods for chemical exposures occur across the life course. Very early exposures may lead to diseases much later on. The current lack of robust science upon which to base high quality expert advice is hampering effective policymaking that leads to further reductions in marine pollution, greater protection of marine life and lowering of risks to human health.
Abstract.
Author URL.
Depledge MH, Tyrrell J, Fleming LE, Holgate ST (2013). Are marine environmental pollutants influencing global patterns of human disease?.
Marine Environmental Research,
83, 93-95.
Abstract:
Are marine environmental pollutants influencing global patterns of human disease?
Thousands of toxic chemicals, many of which pollute marine ecosystems, potentially cause diseases, but building a consensus view of the significance of human body burdens of environmental chemicals is proving difficult. Causative mechanisms are often lacking. Older members of the population, of which there are increasing numbers worldwide, accumulate higher body burdens than the young, and may be especially at risk. It also remains unclear when crucially sensitive periods for chemical exposures occur across the life course. Very early exposures may lead to diseases much later on. The current lack of robust science upon which to base high quality expert advice is hampering effective policymaking that leads to further reductions in marine pollution, greater protection of marine life and lowering of risks to human health. © 2012 Elsevier Ltd.
Abstract.
Tyrrell J, Melzer D, Henley W, Galloway TS, Osborne NJ (2013). Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001-2010.
Environ Int,
59, 328-335.
Abstract:
Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001-2010.
Low level chronic exposure to toxicants is associated with a range of adverse health effects. Understanding the various factors that influence the chemical burden of an individual is of critical importance to public health strategies. We investigated the relationships between socioeconomic status (SES) and bio-monitored chemical concentration in five cross-sectional waves of the U.S. National Health and Nutrition Examination Survey (NHANES). We utilised adjusted linear regression models to investigate the association between 179 toxicants and the poverty income ratio (PIR) for five NHANES waves. We then selected a subset of chemicals associated with PIR in 3 or more NHANES waves and investigated potential mediating factors using structural equation modelling. PIR was associated with 18 chemicals in 3 or more NHANES waves. Higher SES individuals had higher burdens of serum and urinary mercury, arsenic, caesium, thallium, perfluorooctanoic acid, perfluorononanoic acid, mono(carboxyoctyl) phthalate and benzophenone-3. Inverse associations were noted between PIR and serum and urinary lead and cadmium, antimony, bisphenol a and three phthalates (mono-benzyl, mono-isobutyl, mono-n-butyl). Key mediators included fish and shellfish consumption for the PIR, mercury, arsenic, thallium and perfluorononanoic acid associations. Sunscreen use was an important mediator in the benzophenone-3/PIR relationship. The association between PIR and cadmium or lead was partially mediated by smoking, occupation and diet. These results provide a comprehensive analysis of exposure patterns as a function of socioeconomic status in US adults, providing important information to guide future public health remediation measures to decrease toxicant and disease burdens within society.
Abstract.
Author URL.
Tyrrell J, Galloway TS, Abo-Zaid G, Melzer D, Depledge MH, Osborne NJ (2013). High urinary tungsten concentration is associated with stroke in the National Health and Nutrition Examination Survey 1999-2010.
PLoS One,
8(11).
Abstract:
High urinary tungsten concentration is associated with stroke in the National Health and Nutrition Examination Survey 1999-2010.
BACKGROUND: in recent years there has been an exponential increase in tungsten demand, potentially increasing human exposure to the metal. Currently, the toxicology of tungsten is poorly understood, but mounting evidence suggests that both the elemental metal and its alloys have cytotoxic effects. Here, we investigate the association between tungsten and cardiovascular disease (CVD) or stroke using six waves of the National Health and Nutrition Examination Survey (NHANES). METHODS: We investigated associations using crude and adjusted logistic regression models in a cohort of 8614 adults (18-74 years) with 193 reported stroke diagnoses and 428 reported diagnoses of CVD. We also stratified our data to characterize associations in a subset of younger individuals (18-50 years). RESULTS: Elevated tungsten concentrations were strongly associated with an increase in the prevalence of stroke, independent of typical risk factors (Odds Ratio (OR): 1.66, 95% Confidence Interval (95% CI): 1.17, 2.34). The association between tungsten and stroke in the young age category was still evident (OR: 2.17, 95% CI: 1.33, 3.53). CONCLUSION: This study represents the most comprehensive analysis of the human health effects of tungsten to date. Individuals with higher urinary tungsten concentrations have double the odds of reported stroke. We hypothesize that the pathological pathway resulting from tungsten exposure may involve oxidative stress.
Abstract.
Author URL.
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.
Tyrrell JS, Yaghootkar H, Freathy RM, Hattersley AT, Frayling TM (2013). Paternal Diabetes is Associated with Lower Birth Weight in the UK Biobank Study of 500,000 Individuals.
Author URL.
2012
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.
2011
Tyrrell JS, Morton C, Campbell SM, Curnow A (2011). Comparison of protoporphyrin IX accumulation and destruction during methylaminolevulinate photodynamic therapy of skin tumours located at acral and nonacral sites.
Br J Dermatol,
164(6), 1362-1368.
Abstract:
Comparison of protoporphyrin IX accumulation and destruction during methylaminolevulinate photodynamic therapy of skin tumours located at acral and nonacral sites.
BACKGROUND: Topical photodynamic therapy (PDT) is successful in the treatment of nonmelanoma skin cancers and associated precancers, but efficacy is significantly reduced in actinic keratosis lesions not located on the face or scalp. OBJECTIVES: to compare the changes in protoporphyrin IX (PpIX) fluorescence in lesions undergoing routine methylaminolevulinate (MAL) PDT and the clinical outcome observed 3 months after treatment in lesions located at acral and nonacral sites. METHODS: This study was a noninterventional, nonrandomized, observational study, which monitored changes in PpIX fluorescence in 200 lesions during standard dermatological MAL-PDT. These data were subsequently analysed in terms of lesions located at acral and nonacral sites. RESULTS: Clinical clearance was significantly reduced (P < 0·01) in acral skin lesions when compared with lesions located at nonacral sites. The accumulation and destruction of PpIX fluorescence was significantly reduced in these acral lesions (P < 0·05 and P < 0·001, respectively). Specifically, lesion location at acral sites significantly reduced changes in PpIX fluorescence in actinic keratosis lesions during MAL-PDT (P < 0·01 and P < 0·05). CONCLUSIONS: These data suggest that reduced PpIX accumulation and the subsequent reduction in PpIX photobleaching within acral lesions result in the reduced responsiveness of these lesions to MAL-PDT. Future work should therefore aim to improve photosensitizer accumulation/photobleaching within lesions located at acral sites.
Abstract.
Author URL.
Allen J, Tyrrell J, Morton C, Campbell S, Curnow A (2011). Comparison of protoporphyrin IX accumulation and photobleaching during methyl-aminolevulinate photodynamic therapy of skin tumours located at acral and non-acral sites. Photodiagnosis and Photodynamic Therapy, 8(2).
Tyrrell J, Campbell SM, Curnow A (2011). Monitoring the accumulation and dissipation of the photosensitizer protoporphyrin IX during standard dermatological methyl-aminolevulinate photodynamic therapy utilizing non-invasive fluorescence imaging and quantification.
Photodiagnosis Photodyn Ther,
8(1), 30-38.
Abstract:
Monitoring the accumulation and dissipation of the photosensitizer protoporphyrin IX during standard dermatological methyl-aminolevulinate photodynamic therapy utilizing non-invasive fluorescence imaging and quantification.
BACKGROUND: Dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) is utilized to successfully treat dermatological conditions. This study monitored fluorescence changes attributed to the accumulation and destruction of the photosensitizer, protoporphyrin IX (PpIX), at several different stages during the first and second treatments of clinical dermatological MAL-PDT. METHODS: a commercially available, non-invasive, fluorescence imaging system (Dyaderm, Biocam, Germany) was utilized to monitor fluorescence changes during the first and second MAL-PDT treatments in seventy-five lesions. RESULTS: the clinical data indicated statistically significant increases in fluorescence within lesions following the application of MAL for both treatments (P
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Curnow A, Tyrrell J, Campbell S (2011). Non-invasive monitoring of dermatological PDT. Photodiagnosis and Photodynamic Therapy, 8(2), 144-145.
Tyrrell J, Thorn C, Shore A, Campbell S, Curnow A (2011). Oxygen saturation and perfusion changes during dermatological methyl-aminolevulinate photodynamic therapy. British Journal of Dermatology
Tyrrell J, Campbell SM, Curnow A (2011). The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy.
J Photochem Photobiol B,
103(1), 1-7.
Abstract:
The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy.
Methyl aminolevulinate photodynamic therapy (MAL-PDT) is utilized to successfully treat licensed indications (e.g. actinic keratosis (AK), superficial basal cell carcinoma (sBCC) and Bowen's disease (BD)) in the UK. Air cooling devices (ACD) are commonly utilized as a method of pain relief, however the effect of this on treatment outcome has never been extensively investigated. This non-randomized, retrospective observational controlled study investigated whether the application of the ACD limited photosensitiser (protoporphyrin IX - PpIX) photobleaching during irradiation and/or subsequent clinical outcome. Patients utilizing the ACD throughout treatment were observed to undergo significantly less PpIX photobleaching than the control group (P
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2010
Campbell SM, Tyrrell J, Marshall R, Curnow A (2010). Effect of MAL-photodynamic therapy on hypertrophic scarring.
Photodiagnosis Photodyn Ther,
7(3), 183-188.
Abstract:
Effect of MAL-photodynamic therapy on hypertrophic scarring.
BACKGROUND: Patients with localised scleroderma receiving aminolevulinic acid (ALA)/methyl aminolevulinic acid (MAL)-photodynamic therapy (PDT) were noted to show a reduction in skin tightness, suggesting that this therapy reduces skin sclerosis. Karrer and colleagues treated patients with 5-ALA-PDT once or twice weekly for 3-6 months and in all patients the therapy was reported to be highly effective for sclerotic plaques. In view of the potential benefit of PDT in reducing skin sclerosis, the following study looks at the possible clinical and histological effects of topical PDT on the mechanism of scarring, looking particularly at hypertrophic scars. METHODS: Patients with long standing hypertrophic scars were treated with MAL-PDT on two occasions at week apart, and repeated for 3 sessions at 6-weekly intervals. PDT effect was studied by means of fluorescence imaging throughout the treatment and biopsies were taken prior to and 6 weeks post-treatment to observe histological changes. RESULTS AND CONCLUSIONS: Six weeks following the treatment the scarred areas had significantly softened and become more flexible clinically and histologically there had been a significant increase in elastin fibres. This suggests that ALA/MAL-PDT may be a useful treatment or adjuvant therapy in the treatment of scarring.
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Tyrrell J, Campbell S, Curnow A (2010). Protoporphyrin IX photobleaching during the light irradiation phase of standard dermatological methyl-aminolevulinate photodynamic therapy.
Photodiagnosis Photodyn Ther,
7(4), 232-238.
Abstract:
Protoporphyrin IX photobleaching during the light irradiation phase of standard dermatological methyl-aminolevulinate photodynamic therapy.
BACKGROUND: Methyl-aminolevulinate photodynamic therapy (MAL-PDT) is a successful treatment for non-melanoma skin cancers in the UK. Monitoring the photobleaching of the photosensitiser, protoporphyrin IX (PpIX) during treatment has been demonstrated to indicate the efficacy of the treatment. This study investigated photobleaching during light irradiation. METHODS: a validated non-invasive fluorescence imaging system was utilised to monitor changes in PpIX fluorescence during light irradiation. Fifty patients were recruited to this study, with patients monitored before, during (forty patients at the half way stage and ten at regular intervals in the initial phase of treatment) and after light irradiation. RESULTS: Phased PpIX photobleaching was observed during light irradiation with a significantly greater change (P
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Tyrrell JS, Campbell SM, Curnow A (2010). The relationship between protoporphyrin IX photobleaching during real-time dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) and subsequent clinical outcome.
Lasers Surg Med,
42(7), 613-619.
Abstract:
The relationship between protoporphyrin IX photobleaching during real-time dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) and subsequent clinical outcome.
BACKGROUND AND OBJECTIVE: the relationship between protoporphyrin IX (PpIX) photobleaching and cellular damage during aminolevulinic (ALA) photodynamic therapy (PDT) has been studied at the cellular level. This study assessed the capability of a non-invasive fluorescence imaging system (Dyaderm, Biocam, Germany), to monitor changes in PpIX during real time methyl-aminolevulinate (MAL) PDT in dermatological lesions, and thus to act as a predictive tool in terms of observed clinical outcome post-treatment. MATERIALS AND METHODS: Patients attending Royal Cornwall Hospital (Truro, UK) for MAL-PDT to licensed lesions (actinic keratosis, Bowen's disease, and basal cell carcinoma) were monitored using the pre-validated non-invasive fluorescence imaging system. Patients were imaged at three distinct time points: prior to the application of MAL, after the 3 hours of MAL application and immediately following light irradiation. The fluorescence intensity of the images were analysed with image analysis software and the percentage change in fluorescence during light irradiation was related to the clinical outcome observed 3 months following treatment. In total 100 patients underwent at least one session of MAL-PDT. RESULTS: Significantly higher levels of change in PpIX fluorescence during light irradiation (P0.500) was observed in the total levels of PpIX recorded after MAL application in patients undergoing partial and complete clearance at 3 months. CONCLUSIONS: PpIX photobleaching is indicative of the level of cellular damage PDT treatment will induce and therefore the clinical outcome expected within patients. This study indicated the potential of the commercially available fluorescence imaging system investigated to predict treatment success at the time of light irradiation and in the future it may be possible to employ it to individualise treatment parameters to improve dermatological PDT efficacy/outcome.
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Tyrrell J, Campbell S, Curnow A (2010). Validation of a non-invasive fluorescence imaging system to monitor dermatological PDT.
Photodiagnosis Photodyn Ther,
7(2), 86-97.
Abstract:
Validation of a non-invasive fluorescence imaging system to monitor dermatological PDT.
BACKGROUND: Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) involves selective accumulation of a photosensitiser, protoporphyrin IX (PpIX), primarily in tumour tissue, which in combination with visible light and tissue oxygen results in reactive oxygen species (ROS) production and thus cellular destruction. METHODS: a non-invasive fluorescence imaging system (Dyaderm, Biocam, Germany) has been employed to acquire colour (morphological) and fluorescent (physiological) images simultaneously during dermatological PDT. This system had been previously utilised for fluorescence diagnosis, however, here changes in PpIX concentration within the skin lesions and normal tissue were followed after MAL application. Measurements were also recorded from a synthetic PpIX standard. RESULTS: Results indicated that imaging distance, imaging angle, position of the region of interest and light conditions all altered the PpIX levels acquired from the synthetic PpIX standard. The imaging system was therefore adapted and a standard operating procedure developed allowing reproducible images of dermatological lesions to be acquired. Different concentrations of synthetic PpIX were analysed with the system and a linear relationship was observed between the PpIX concentration and the mean greyscale value calculated for the images acquired up to 10 microM. CONCLUSIONS: the Dyaderm imaging system can now be used reproducibly with confidence to semi-quantify PpIX (within the range of 0-10 microM) within dermatological lesions using the standard operating procedure derived from this work.
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2009
Pye A, Dogra Y, Tyrrell J, Winyard PG, Curnow A (2009). Photodynamic therapy with aminolevulinic acid and iron chelators: a clinical example of redox signaling. In Jacob C, Winyard PG, Wiley-VCH (Eds.) Redox Signaling and Regulation in Biology and Medicine, Weinheim, Germany: , 351-372.
Tyrrell J, Campbell S, Curnow A (2009). The utilization of a non-invasive fluorescence imaging system to follow clinical dermatological MAL-PDT. Photodynamic Therapy - Back to the Future.
Abstract:
The utilization of a non-invasive fluorescence imaging system to follow clinical dermatological MAL-PDT
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2008
Tyrrell J, Shore A, Curnow A (2008). Monitoring clinical dermatological photodynamic therapy: validation of a noninvasive fluorescence imaging system.
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2007
Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrín D, et al (2007). Structural basis for complement factor H linked age-related macular degeneration.
J Exp Med,
204(10), 2277-2283.
Abstract:
Structural basis for complement factor H linked age-related macular degeneration.
Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.
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Prosser B, Johnson S, Roversi P, Herbert A, Blaum BS, Uhrin D, Tyrrell J, Clark S, Tarelli E, Barlow P, et al (2007). Towards a structural basis for complement factor H linked age-related macular degeneration.
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