Abstract
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.
Highlights
There are strong epidemiological associations between disrupted circadian rhythms, sleep duration and disease
Using the first release of the UK Biobank study, which combines detailed measurements and questionnaire data with genetic data, we investigate the genetics of two self-report sleep measures, chronotype and average sleep duration, in 128,266 white British individuals
Associated variants are located near genes implicated in circadian rhythm regulation (RGS16, PER2), near a serotonin receptor gene (HTR6) and another gene (INADL) encoding a protein thought to be important in photosensitive retinal cells, cells known to communicate with the brain’s primary circadian pacemaker
Summary
There are strong epidemiological associations between disrupted circadian rhythms, sleep duration and disease. There are clear daily cyclical patterns in core body temperature, hormonal and most other biological systems [1] These cycles are important for many molecular and behavioural processes. While each individual has an endogenous circadian rhythm, the timing of these rhythms varies across individuals Those with later circadian rhythms tend to sleep best with a late bedtime and late rising time and are often referred to as an “owl” or as an “evening” person. The remainder of the population falls in between these extremes This dimension of circadian timing, or chronotype, is one behavioural consequence of these underlying cycles. Chronotype can be assessed by questionnaire and is considered a useful tool for studying circadian rhythms [2,3]
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