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that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009903,147; African,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009122,571; Latin American,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200938,962; East Asian,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200913,551; and South Asian,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20091,716 ancestries). 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 chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights\u2014together with neuroscience, biology and data science\u2014closer.\n                  <\/jats:p>","DOI":"10.1038\/s41591-023-02653-5","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T06:04:35Z","timestamp":1701929075000},"page":"3184-3192","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":201,"title":["Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-6391","authenticated-orcid":false,"given":"Hang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8820-2659","authenticated-orcid":false,"given":"Rachel L.","family":"Kember","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0540-6080","authenticated-orcid":false,"given":"Joseph D.","family":"Deak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvanus","family":"Toikumo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope A.","family":"Lind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Farajzadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander S.","family":"Hatoum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-3001","authenticated-orcid":false,"given":"Travis T.","family":"Mallard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6379-386X","authenticated-orcid":false,"given":"Jiayi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1370-3149","authenticated-orcid":false,"given":"Keira J. 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M.B.S. has in the past 3\u2009years 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 United States patent 10,900,082 titled: \u2018Genotype-guided dosing of opioid agonists,\u2019 issued 26 January 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 (United Kingdom), 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 University of Sydney. The Brain and Mind Centre 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\u2009M Australian Government-funded Project Synergy (2017\u201320; a 3\u2009year 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 principal investigator 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. D.D. has received a speaker fee from Medici Nordic. All other authors report no biomedical financial interests or potential conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}