Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
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ABSTRACT:
SUBMITTER: Dashti HS
PROVIDER: S-EPMC6405943 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.
Dashti Hassan S HS Jones Samuel E SE Wood Andrew R AR Lane Jacqueline M JM van Hees Vincent T VT Wang Heming H Rhodes Jessica A JA Song Yanwei Y Patel Krunal K Anderson Simon G SG Beaumont Robin N RN Bechtold David A DA Bowden Jack J Cade Brian E BE Garaulet Marta M Kyle Simon D SD Little Max A MA Loudon Andrew S AS Luik Annemarie I AI Scheer Frank A J L FAJL Spiegelhalder Kai K Tyrrell Jessica J Gottlieb Daniel J DJ Tiemeier Henning H Ray David W DW Purcell Shaun M SM Frayling Timothy M TM Redline Susan S Lawlor Deborah A DA Rutter Martin K MK Weedon Michael N MN Saxena Richa R
Nature communications 20190307 1
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 < 5 × 10<sup>-8</sup>; 43 loci at p < 6 × 10<sup>-9</sup>). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10<sup>-4</sup>), and 55 signals show ...[more]
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Project description: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 oversleeping 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.
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Project description:Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10-4) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10-4). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: -0.91, SE = 0.18, p = 8.2 × 10-7), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10-8). Our results advocate the value of physical activity for reducing blood pressure.
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