Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature. ### Competing Interest Statement H.R.K. 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; and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. M.B.S. has in the past 3□years been a consultant for Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, Epivario, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, Roche/Genentech and Oxeia Biopharmaceuticals. M.B.S. has stock options in Oxeia Biopharmaceuticals and Epivario. He also receives payment from the following entities for editorial work: Biological Psychiatry (published by Elsevier), Depression and Anxiety (published by Wiley) and UpToDate. J.G. and H.R.K. hold US patent 10,900,082 titled: Genotype-guided dosing of opioid agonists, issued January 26, 2021. J.G. is paid for his editorial work on the journal Complex Psychiatry. J.H.K. has consulting agreements (less than US$10,000 per year) with the following: AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, Otsuka America, Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries and Taisho Pharmaceutical Co., Ltd. J.H.K. serves on the scientific advisory boards of Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC., EpiVario, Inc., Lohocla Research Corporation, PsychoGenics, Inc.; is on the board of directors of Inheris Biopharma, Inc.; has stock options with Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, Inc., EpiVario, Inc. and Terran Life Sciences; and is editor of Biological Psychiatry with income greater than $10,000. I.B.H. is the Co-Director of Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. J.W.S. is a member of the Leon Levy Foundation Neuroscience Advisory Board, the Scientific Advisory Board of Sensorium Therapeutics (with equity), and has received grant support from Biogen, Inc. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. All other authors report no biomedical financial interests or potential conflicts of interest. ### Funding Statement This research used data from the Million Veteran Program and was supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant #I01CX001849, #I01BX004820, #I01BX003341, and the VA Cooperative Studies Program (CSP) study #575B, MVP004, and MVP025. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. Supported also by NIH (NIAAA) P50 AA12870 (J.H.K.) and K01 AA028292 (R.L.K.), a NARSAD Young Investigator Grant 27835 from the Brain & Behavior Research Foundation (H.Z.), NCI R21 CA252916 (H.Z.), R01 AA026364 (J.G.), NIAAA T32 AA028259 (J.D.D.), NIMH R01 MH124839 (L.M.H.), NIAAA K01 AA030083 (A.S.H.), NIDA K01 DA051759 (E.C.J.), TRDRP (T29KT0526, T32IR5226, S.S.R.) and NIDA DP1 DA054394 (S.S.R.). This research used data from UK Biobank (project ID: 41910), a population-based sample of participants whose contributions we gratefully acknowledge. The data access is supported by Yale SCORE pilot grant (U54AA027989). We want to acknowledge the participants and investigators of the FinnGen study. D.D. was supported by the Novo Nordisk Foundation (NNF20OC0065561), the Lundbeck Foundation (R344-2020-1060). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003), NIH/NIMH (1U01MH109514-01 and 1R01MH124851-01 to A.D.B.) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). The Australian Genetics of Depression Study (AGDS) was primarily funded by the National Health and Medical Research Council (NHMRC) of Australia Grant No. 1086683 to N.G.M. N.G.M is supported by a NHMRC Investigator Grant (No. APP 1172990). We are indebted to all of the participants for giving their time to contribute to this study. We wish to thank all the people who helped in the conception, implementation, media campaign and data cleaning. We thank Richard Parker, Simone Cross, and Lenore Sullivan for their valuable work coordinating all the administrative and operational aspects of the AGDS project. We would also like to thank the research participants for making this work possible. The Australian Genetics of Bipolar Disorder Study (GBP) data collection was funded and data analysis was supported by the Australian NHMRC (No. APP1138514) to S.E.M. S.E.M. is supported by a NHMRC Investigator Grant (No. APP1172917). We thank the participants for giving their time and support for this project. We acknowledge and thank M. Steffens for her generous donations and fundraising support. The NHMRC (APP10499110) and the NIH (K99R00, R00DA023549) funded the 19Up study. Genotyping was funded by the NHMRC (389891). We thank the twins and their families for their willing participation in our studies. Funding for the Australian adult twin studies in which information on alcohol use and smoking status was obtained came from the US NIH (AA07535, AA07728, AA11998, AA13320, AA13321, AA14041, AA17688, DA012854 and DA019951); the Australian NHMRC (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485 and 552498); and the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016 and DP0343921). We acknowledge the work over many years of staff of the Genetic Epidemiology group at QIMR Berghofer Medical Research Institute (formerly the Queensland Institute of Medical Research) in managing the studies which generated the data used in this analysis. We also acknowledge and appreciate the willingness of study participants to complete multiple, and sometimes lengthy, questionnaires and interviews. Many of the participants were contacted originally through the Australian Twin Registry. This research also used summary data from the Psychiatric Genomics Consortium (PGC) Substance Use Disorders (SUD) working group. The PGC-SUD is supported by NIH grant R01DA054869. PGC-SUD gratefully acknowledges its contributing studies and the participants in those studies, without whom this effort would not be possible. We acknowledge the Penn Medicine BioBank (PMBB) for providing data and thank the patient-participants of Penn Medicine who consented to participate in this research program. We would also like to thank the PMBB team and Regeneron Genetics Center for providing genetic variant data for analysis. The PMBB is approved under IRB protocol# 813913 and supported by Perelman School of Medicine at University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the NIH under CTSA award number UL1TR001878. This study was supported in part through the resources and staff expertise provided by the Charles Bronfman Institute for Personalized Medicine and The BioMe Biobank Program at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the NIH under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. ### 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: The Central Veterans Affairs Institutional Review Board (IRB) and site-specific IRBs approved the MVP study. All relevant ethical regulations for work with human subjects were followed in the conduct of the study and informed consent was obtained from all participants. The iPSYCH study was approved by the Scientific Ethics Committee in the Central Denmark Region (Case No 1-10-72-287-12) and the Danish Data Protection Agency. 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 The full summary-level association data from the meta-analysis are available upon request to the corresponding authors and through dbGaP (accession number phs001672).