Sleep is an essential human function but its regulation is poorly understood. Identifying genetic variants associated with quality, quantity and timing of sleep will provide biological insights into the regulation of sleep and potential links with disease. Using accelerometer data from 85,670 individuals in the UK Biobank, we performed a genome-wide association study of 8 accelerometer-derived sleep traits. We identified 47 genetic associations across the sleep traits (P<5x10 -8 ) and replicated our findings in 5,819 individuals from 3 independent studies. These included 10 novel associations for sleep duration and 26 for sleep quality. Most newly identified variants were associated with a single sleep trait, but variants previously associated with restless legs syndrome were observed to be associated with multiple sleep traits. As a group, sleep quality loci were enriched for serotonin processing genes and all sleep traits were enriched for cerebellar-expressed genes. These findings provide new biological insights into sleep characteristics.

word summaryFibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21's therapeutic potential. IntroductionFGF21 is a hormone secreted primarily by the liver whose multiple functions include signalling to the paraventricular nucleus of the hypothalamus to suppress sugar and alcohol intake [1,2], stimulating insulin-independent glucose uptake by adipocytes [3] and acting as an insulin sensitizer [4]. These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6]. An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7]. A recent study suggested that FGF21 analogues may alter not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/214700 doi: bioRxiv preprint first posted online Nov. 6, 2017; blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3]. Subsequent studies have confirmed these findings in mice [10] and shown similar effects in non human primates, including improvement of glucose tolerance and slight weight loss in diabetic rhesus monkeys [11], but other studies are less conclusive [5].Recent studies have shown that FGF21 affects the balance of macronutrients consumed. Studies in mice and non human primates show that genetically and pharmacologically raising FGF21 levels suppresses sugar and alcohol intake [1,2]. Three human genetic studies have shown that the minor A allele at rs838133 (A/G, Minor Allele Frequency=44.7%), which results in a synonymous change to the first exon of FGF21, is associated with higher carbohydrate and lower...

Susceptibility to obesity in today's environment has a strong genetic component.Lower socioeconomic position (SEP) is associated with a higher risk of obesity but it is not known if it accentuates genetic susceptibility to obesity. We aimed to use up to 120,000 individuals from the UK Biobank study to test the hypothesis that measures of socioeconomic position accentuate genetic susceptibility to obesity. We used the Townsend deprivation index (TDI) as the main measure of socioeconomic position, and a 69-variant genetic risk score (GRS) as a measure of genetic susceptibility to obesity. We also tested the hypothesis that interactions between BMI genetics and socioeconomic position would result in evidence of interaction with individual measures of the obesogenic environment and behaviours that correlate strongly with socioeconomic position, even if they have no obesogenic role. These measures included self-reported TV watching, diet and physical activity, and an objective measure of activity derived from accelerometers. We performed several negative control tests, including a simulated environment correlated with BMI but not TDI, and sun protection use. We found evidence of gene-environment interactions with TDI (Pinteraction=3x10 -10 ) such that, 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 1.73m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMIraising alleles was associated with approximately 2.9 kg extra weight. We also observed evidence of interaction between sun protection use and BMI genetics, suggesting that residual confounding may result in evidence of non-causal interactions. Our findings provide evidence that relative social deprivation best captures aspects of the obesogenic environment that accentuate the genetic predisposition to obesity in the UK.

Women with X chromosome aneuploidy such as 45,X (Turner syndrome) or 47,XXX (Triple X syndrome) present with a range of characteristics including differences in stature, an increased risk of cardiovascular disease and premature ovarian insufficiency. Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, biased ascertainment of cases may mean that the penetrance of phenotypes is overestimated. We aimed to characterise the prevalence and phenotypic consequences of X chromosome aneuploidy in a large population of older adults. We detected 30 women with 45,X, 186 with mosaic 45,X/46,XX and 110 with 47,XXX in 245,203 women from UK Biobank, using SNP array data. The phenotypic features of women with full aneuploidy (whether 45,X or 47,XXX) were similar to those previously reported.Consistent with the recognised Turner syndrome phenotype, those with 45,X were 17.2cmshorter than controls and 53% did not go through menarche. Similarly, the phenotype of women with 47,XXX included increased height (on average 5.3cm taller than controls, P = 1 . CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/177659 doi: bioRxiv preprint first posted online Aug. 18, 2017; x 10 -18 ), earlier menopause age (on average 5.12 years earlier than controls, P = 1.2 x 10 -14 )and a lower fluid intelligence (on average 24% lower than controls, P = 3.7 x 10 -8 ). In contrast, women with 45,X/46,XX mosaicism had a very mild phenotype; were not as short, had a normal reproductive lifespan and birth rate, with no reported cardiovascular complications. This study characterises X chromosome aneuploidy phenotypes in an adult population-based sample of older individuals and suggests that clinical management of women with a 45,X/46,XX mosaic karyotype should be minimal, particularly those identified incidentally.