Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants underlying AUD. However, there are few whole-exome sequencing (WES) studies of AUD. We analyzed WES of 4,530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank (UKB). After quality control, 1,420 AUD cases and 619 controls of European ancestry (EUR) and 1,142 cases and 608 controls of African ancestry (AFR) from Yale-Penn were retained for subsequent analyses. WES data from 415,617 EUR samples (12,861 cases), 6,142 AFR samples (130 cases) and 4,607 South Asian (SAS) samples (130 cases) from UKB were also analyzed. Single-variant association analysis identified the well-known functional variant rs1229984 in ADH1B (P=4.88E-31) and several other common variants in ADH1C. Gene-based tests identified ADH1B (P=1.00E-31), ADH1C (P=5.23E-7), CNST (P=1.19E-6), and IFIT5 (3.74E-6). This study extends our understanding of the genetic basis of AUD.

J.G. is paid for his editorial work on the journal Complex Psychiatry. J.G. and H.R.K. hold US patent 10,900,082 titled: "Genotype-guided dosing of opioid agonists," issued January 26, 2021. H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals, and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics.

The data access is supported by Yale-SCORE on sex differences in AUD pilot grant (U54 AA027989). The authors are supported by grants from the National Institutes of Health (NIH) (R01 AA026364, R01 DA037974, P50 AA012870, R21 CA252916, U54 AA027989R01AA026364, R01AA11330, R01DA12890, R01DA037974, P50AA012870, R21CA252916, U54AA027989, RM1 HG011558, and R01 AA030056) and the Department of Veterans Affairs (1I01CX001849 and I01 BX004820). H.Z. was also supported by a NARSAD Young Investigator grant #27835 from the Brain & Behavior Research Foundation.

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

The Yale-Penn study was approved by Yale Human Research Protection Program and University of Pennsylvania IRB

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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.

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All data produced in the present study are available upon reasonable request to the authors