Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10(-8)), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10(-12)) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10(-10)). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants;thirteen of the chronotype signals remained associated at P<5x10(-8) on meta-analysis and eleven of these reached P< 0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10(-8)). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10(-16)) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10(-9);and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10(-9)). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05);undersleeping and BMI (rG = 0.147, P = 1x10(-5)) and over-sleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans

Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.</p

Cross-translational studies in human and Drosophila identify markers of sleep loss

Inadequate sleep has become endemic, which imposes a substantial burden for public health and safety. At present, there are no objective tests to determine if an individual has gone without sleep for an extended period of time. Here we describe a novel approach that takes advantage of the evolutionary conservation of sleep to identify markers of sleep loss. To begin, we demonstrate that IL-6 is increased in rats following chronic total sleep deprivation and in humans following 30 h of waking. Discovery experiments were then conducted on saliva taken from sleep-deprived human subjects to identify candidate markers. Given the relationship between sleep and immunity, we used Human Inflammation Low Density Arrays to screen saliva for novel markers of sleep deprivation. Integrin αM (ITGAM) and Anaxin A3 (AnxA3) were significantly elevated following 30 h of sleep loss. To confirm these results, we used QPCR to evaluate ITGAM and AnxA3 in independent samples collected after 24 h of waking; both transcripts were increased. The behavior of these markers was then evaluated further using the power of Drosophila genetics as a cost-effective means to determine whether the marker is associated with vulnerability to sleep loss or other confounding factors (e.g., stress). Transcript profiling in flies indicated that the Drosophila homologues of ITGAM were not predictive of sleep loss. Thus, we examined transcript levels of additional members of the integrin family in flies. Only transcript levels of scab, the Drosophila homologue of Integrin α5 (ITGA5), were associated with vulnerability to extended waking. Since ITGA5 was not included on the Low Density Array, we returned to human samples and found that ITGA5 transcript levels were increased following sleep deprivation. These cross-translational data indicate that fly and human discovery experiments are mutually reinforcing and can be used interchangeably to identify candidate biomarkers of sleep loss

Genetic variants in RBFOX3 are associated with sleep latency

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10-08, 6.59 × 10- 08 and 9.17 × 10- 08). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10- 02, 7.0 × 10- 03 and 2.5 × 10- 03; combined meta-analysis P-values=5.5 × 10-07, 5.4 × 10-07 and 1.0 × 10-07). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10-316) and the central nervous system (P-value=7.5 × 10- 321). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitte

Genome-Wide and Abdominal MRI-Imaging Data Provides Evidence that a Genetically Determined Favourable Adiposity Phenotype is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease and Hypertension

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such “favourable adiposity” alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging (MRI) data with genome-wide association studies (GWAS) of body fat % and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity, but a favourable metabolic profile. Consistent with previous studies, individuals carrying more “favourable 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 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, whilst the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified “favourable adiposity” alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in metabolically low risk depots.Diabetes UK RD Lawrence fellowship, European Research Council, Wellcome Trust and Royal Society grant, European Regional Development Fund, Medical Research Council, German Federal Ministry of Education and Research, German Research Foundation, Innovative Medicines Initiative Joint Undertaking, European Union's Seventh Framework Programme, Dutch Science Organisation, Scottish Government Health Directorates, Scottish Funding Council and Medical Research Council UK and the Wellcome Trust

Recommended sleep duration is associated with higher consumption of fruits and vegetables; cross-sectional and prospective analyses from the UK Women’s Cohort Study

Background: High intakes of fruit and vegetable has been shown to protect against diseases and all-cause mortality however, the associations between sleep and fruit and vegetable consumption are not well characterized. This study aims to explore both cross-sectional and prospective associations between sleep duration and fruit and vegetable intakes in UK women. This is the first study to demonstrate the prospective association between sleep duration and fruit and vegetable consumption. Methods: Cross–sectional and prospective data were obtained from the UK Women’s Cohort Study. Sleep duration was assessed by self-report of average hours slept on weekdays and weekends and diet was assessed by a 4-day food diary at baseline and follow-up (~ 4 years later). Sleep duration was categorized as short (≤6 h/d), recommended (7–9 h/d) and long (≥9 h/d). Regression analyses adjusting for age, socio-economic status, smoking, ethnicity and total energy intake were used and restricted cubic spline models were developed to explore potential non-linear associations between sleep duration and fruit and vegetable intakes. Results: In adjusted cross-sectional analyses, short sleepers had on average 17 g/d (95% CI -30 to-4, p = 0.01) and long sleepers had 25 g/d (95% CI -39 to − 12, p < 0.001) less total fruits and vegetables compared to Recommended Sleepers (RS). In adjusted prospective analyses, short sleepers had on average 85 g/d (95% CI -144 to − 26, p = 0.005) less total fruits and vegetables in comparison to RS. Restricted cubic spline models showed that the cross-sectional (p < 0.001) and prospective (p = 0.001) associations between sleep duration and fruit and vegetable intakes were non-linear with women sleeping 7–9 h/d having the highest intakes. Conclusions: Fruit and vegetable consumption differed between sleep duration categories with UK women sleeping the recommended 7–9 h/day having the highest intake of fruits and vegetables in cross-sectional and prospective analyses. These findings suggest that sleeping the recommended duration is associated with higher consumption of fruits and vegetables. Sleep is an overlooked lifestyle factor in relation to fruit and vegetable consumption and more notice is vital. Further studies are required to clarify the underlying mechanisms for these associations

Genetic basis of human circadian rhythm disorders

Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health