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

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.

Two sides of a coin: ecological and chronobiological perspectives of timing in the wild

“…B 372: 20160246 can be well characterized. Extreme human chronotypes are commonly referred to as 'larks'-morning people (those who wake up early and are most alert in the first part of the day) and 'owls'-evening people (those who are most alert in the late evening hours and prefer to go to bed late) [145,146]. This descriptor of chronotype, used in epidemiological and association studies, has revealed a wealth of chronobiological information, including evidence for its partly genetic determination and its links to circadian mechanisms [147,148].…”

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

“…The teams utilized human genome DNA information from about 100,000 individuals whom they queried about their propensity to get up early or sleep in the morning. Interestingly, all three teams led to the same conclusion that genetic variants of RGS16 are closely associated with being a morning person [43][44][45]. These findings provide reason to suspect that RGS16-dependent similar circadian mechanisms operate in humans as well.…”

Sleep quality and OPRM1 polymorphisms: a cross-sectional study among opioid-naive individuals

“…Previous molecular genetic studies have begun to identify genetic variations related to sleep-wake behavior includes 3111 T/C SNP (rs1801260) of the Circadian Locomotor Output Cycles Kaput (CLOCK) gene (Benedetti et al, 2007) and variable-number tandem-repeat (VNTR) polymorphism of the period circadian clock 3 gene (PER3) (Viola et al, 2007). Also, there are a number of recent genome-wide association analyses (GWAS) studies on sleep quality and quantity (Lane et al, 2017;Jones et al, 2016;Byrne et al, 2013). Among the identified polymorphisms within the OPRM1 gene, 118A>G polymorphism is the most frequently studied in the literatures.…”