Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: Summary statistics for the top 10,000 chronotype meta-analysis variants are provided in Supplementary Data 10. The full set of UK Biobank-only chronotype and morning person GWAS summary statistics can be found at http://www.t2diabetesgenes.org/data/ and on the Sleep Disorder Knowledge Portal at http://sleepdisordergenetics.org/informational/data/. Full meta-analysis summary statistics can be requested directly from 23andMe Inc. (see https://research.23andme.com/collaborate/#publication). The GGIR R script used to generate the activity monitor measures (Supplementary Data 14) is available with the online version of this article.Being a morning person is a behavioural indicator of a person’s underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.Medical Research Council (MRC)Wellcome TrustEuropean Research CouncilRoyal SocietyDiabetes Research and Wellness FoundationEuropean Union Seventh Framework Programme (FP7/2007–2013)National Institutes of Health (NIH)University of ManchesterNational Health and Medical Research Council of AustraliaMGH Research Scholar FundDutch Medical Research Foundation grant