Differences in sleep duration, quality, and timing are associated with variation in cognition, health outcomes, and quality of life. Genetic studies may help explain the underlying mechanisms of sleep and its relationships to other conditions. Our previous work highlighted risk loci associated with short (less than 6hrs) and long sleep (more than 9hrs), using data from the UK Biobank and the Million Veteran Program. We build on this work by conducting a genome wide association study (GWAS) and multi-ancestry meta-analysis of sleep duration as a quantitative trait. We used LD score regression (LDSC) to evaluate the correlation between sleep duration and other traits, and genomic structural equation modelling (genomicSEM) to consider the relationships between traits of interest. We identify 234 independent genome-wide significant loci for sleep duration, of which 143 are novel. The average impact of each risk variant amounts to approximately 0.86 minutes (sd=0.19), with a sum total of 220.5 minutes across all genome-wide significant loci. We support previous findings showing the most strongly associated gene is PAX8. Linkage disequilibrium score regression shows that the genetic architecture of sleep duration is largely distinct from other measures of sleep quality and sleep disorders. We see several examples of negative correlation between deleterious traits and the quantitative measure of sleep duration reported here, contrasting with positive associations with long and short sleep (e.g., depression, ADHD, cannabis use disorder, smoking). We derive genomic-SEM models that show short and long sleep load on separate factors, as does overall sleep duration loading alone. This is the largest available GWAS of sleep duration, and the first to extend analyses outside of European ancestry populations. We identify novel loci for sleep duration and provide insight to the shared and unique genetic architecture across multiple sleep and neuropsychiatric traits.

D.J.G reports consulting fees from Apnimen, Inc., Lilly USA, LLC, and Takeda Development Center Americas, Inc. J.G. is paid for editorial work for the journal Complex Psychiatry. M.B.S. has in the past 3 years received consulting income from atai Life Sciences, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Delix Therapeutics, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, Karuna Therapeutics, Lundbeck, Lykos Therapeutics, NeuroTrauma Sciences, Otsuka US, PureTech Health, Roche/Genentech, Sage Therapeutics, Seaport Therapeutics, and Transcend Therapeutics. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from the National Institutes of Health, the Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board of the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. The remaining authors declare no competing interests.

This research has been conducted using the UK Biobank (www. ukbiobank.ac.uk) under application numbers 82087 (PI: Dr Jonathan Coleman). This research is also based on data from the Million Veteran Programme, Office of Research and Development, Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. This work is supported by funding from the UK Medical Research Council and the US Department of Veteran Affairs (CSP575b (NCT02256644) and MERIT (I01CX001849) grants) (both JG and MBS). JG and MBS report support from NIMH R01MH133728-01. D.F.L. was supported by a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation and a Career Development Award from the Veterans Health Administration Office of Research and Development (Grant IK2BX005058) and is Aimee Mann Fellow of Psychiatric Genetics at Yale. J.D.D. was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) T32 AA028259. The authors thank all the volunteers who participated in the UK Biobank and the Million Veteran Programme. We gratefully acknowledge all the studies and databases that made GWAS summary data available.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Source data for this study is from the UK Biobank and the Million Veteran Program, with all necessary ethical approvals in place.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study will be available upon reasonable request to the authors following publication in a peer reviewed journal.