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.

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.

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

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 

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.

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.

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 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. We compared genetic risk scores (GRS), calculated using carriage of 43 susceptibility loci for MS, in 48 cases to 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 9 (17%), progressive symptoms in 3 (6%): 2 (4%) patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 x 10-4, 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 were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.

BACKGROUND: We assessed whether body mass index (BMI) affects social and socio-economic outcomes. METHODS: We used Mendelian randomization (MR), non-linear MR and non-genetic and MR within-sibling analyses, to estimate relationships of BMI with six socio-economic and four social outcomes in 378 244 people of European ancestry in UK Biobank. RESULTS: in MR of minimally related individuals, higher BMI was related to higher deprivation, lower income, fewer years of education, lower odds of degree-level education and skilled employment. Non-linear MR suggested both low (bottom decile, 24.6 kg/m2) BMI, increased deprivation and reduced income. Non-genetic within-sibling analysis supported an effect of BMI on socio-economic position (SEP); precision in within-sibling MR was too low to draw inference about effects of BMI on SEP. There was some evidence of pleiotropy, with MR Egger suggesting limited effects of BMI on deprivation, although precision of these estimates is also low. Non-linear MR suggested that low BMI (bottom three deciles, 30.7 kg/m2) reduces the odds of cohabitation in women. Both non-genetic and MR within-sibling analyses supported this sex-specific effect of BMI on cohabitation. In men only, higher BMI was related to lower participation in leisure and social activities. There was little evidence that BMI affects visits from friends and family or having someone to confide in. CONCLUSIONS: BMI may affect social and socio-economic outcomes, with both high and low BMI being detrimental for SEP, although larger within-family MR studies may help to test the robustness of MR results in unrelated individuals. Triangulation of evidence across MR and within-family analyses supports evidence of a sex-specific effect of BMI on cohabitation.

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.
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. 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.
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. 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.
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. 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.
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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.

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.

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.

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.

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.

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.

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 ), 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. −14

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.

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.

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.

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

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.

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 

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.

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.

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.

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.

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.

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 

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 

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.

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.

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.

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.

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.

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%,

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.

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.

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.

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 

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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

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.

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.

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.