The Relationship between Alcohol- and Sleep-related Traits: Results from Polygenic Risk Score Analyses and Mendelian Randomization Studies

Background Epidemiologic studies have shown an association between sleep abnormalities and alcohol-related traits. Recent genome-wide association studies (GWAS) have identified genetic variants associated with sleep-related traits, including insomnia and sleep duration, and with alcohol-related phenotypes, including alcohol use disorder (AUD) and level of alcohol consumption. Objectives We investigated whether genetic risk for insomnia and sleep duration abnormalities are associated with AUD and alcohol consumption. We also evaluated the causal relationships between sleep- and alcohol-related traits. Methods Individual level phenotype and genotype data from the Million Veteran Program was used. Polygenic risk scores (PRS) were computed using summary statistics from two recent discovery GWAS of insomnia (N=453,379 European-ancestry (EA) individuals) and sleep duration (N=446,118 EAs) and tested for association with lifetime AUD diagnosis (cases, N=34,658 EAs) and past-year Alcohol Use Disorders Identification Test-Consumption scale scores (AUDIT-C, N=200,680 EAs). Bi-directional two-sample Mendelian Randomization (MR) analyses assessed causal associations between the two sleep traits and the two alcohol-related traits. Results Insomnia PRS was positively associated with AUD at 2/9 PRS thresholds, with p<0.01 being the most significant (OR = 1.02, p = 3.48 × 10−5). Conversely, insomnia PRS was negatively associated with AUDIT-C at 6/9 PRS thresholds (most significant threshold being p=0.001 (β = - 0.02, p = 5.6 × 10−8). Sleep duration PRS was not associated with AUD, but was positively associated with AUDIT-C at 2/9 PRS thresholds, with the most significant threshold being p = 1 × 10−6 (β = 0.01, p = 0.0009). MR analyses supported a significant positive causal effect of insomnia on AUD (14 SNPs; beta = 104.14; SE = 16.19; p = 2.22 × 10−5), although with significant heterogeneity. MR analyses also provided nominal evidence of a causal effect of AUD on insomnia (10 SNPs; beta = 0.01; SE = 0.007; p = 0.01). Finally, MR analyses showed that decreased sleep duration had a causal effect on the risk of AUD (27 SNPs; beta = -63.05; SE = 3.54; p = 4.55 × 10−16) and was robust to sensitivity analyses. Conclusion The genetic risk for insomnia shows pleiotropy with AUD, and sleep continuity abnormalities have a causal influence on the development of AUD. ### Competing Interest Statement Dr. Chakravorty has received research support from AstraZeneca Pharmaceuticals and Teva Pharma. Dr. Gehrman has been a consultant for Eight Sleep, Fisher Wallace Laboratories, Eisai, Inc, and Idorsia Pharmaceuticals, Inc. He has obtained research support from Merck Co. Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals, a consultant to Sobrera Pharmaceuticals, the recipient of research funding and medication supplies for an investigator initiated study from Alkermes, a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka, and a holder of U.S. patent 10,900,082. The other authors do not report any actual or potential conflict of interest. ### Funding Statement This work was supported by the following grants: 1IK2CX000855 (S.C.); 1 I01 CX001957 (S.C.); I01 BX003341 (H.R.K); R01 HL143790 (P.R.G), R01 NR018836 (P.R.G.); 1K01 AA028292 (R.L.K.); and the Veterans Integrated Service Network 4 Mental Illness Research, Education, and Clinical Center. The content of this publication does not represent the views of the Department of Veterans Affairs, the US government, Perelman School of Medicine, or other participating institutions. ### Author Declarations 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: UKBiobank GWAS summary statistics is available within GWAS catalog. The MVP study followed all relevant ethical regulations for research with human subjects and obtained informed consent from all participants. The VA Central IRB gave approval for the primary study from where the alcohol-related GWAS summary statistics were extracted. 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. Yes 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). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.