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

Hang Zhou*, Rachel L. Kember, Joseph D. Deak, Heng Xu, Sylvanus Toikumo, Kai Yuan, Penelope A. Lind, Leila Farajzadeh, Lu Wang, Alexander S. Hatoum, Jessica Johnson, Hyunjoon Lee, Travis T. Mallard, Jiayi Xu, Keira J.A. Johnston, Emma C. Johnson, Trine Tollerup Nielsen, Marco Galimberti, Cecilia Dao, Daniel F. LeveyCassie Overstreet, Enda M. Byrne, Nathan A. Gillespie, Scott Gordon, Ian B. Hickie, John B. Whitfield, Ke Xu, Hongyu Zhao, Laura M. Huckins, Lea K. Davis, Sandra Sanchez-Roige, Pamela A.F. Madden, Andrew C. Heath, Sarah E. Medland, Nicholas G. Martin, Tian Ge, Jordan W. Smoller, David M. Hougaard, Anders D. Børglum, Ditte Demontis, John H. Krystal, J. Michael Gaziano, Howard J. Edenberg, Arpana Agrawal, Hongyu Zhao, Amy C. Justice, Murray B. Stein, Henry R. Kranzler, Joel Gelernter*, Million Veteran Program

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

15 Citations (Scopus)

Abstract

Problematic alcohol use (PAU), a trait 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 = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 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—together with neuroscience, biology and data science—closer.

Original languageEnglish
JournalNature Medicine
Volume29
Issue12
Pages (from-to)3184-3192
Number of pages9
ISSN1078-8956
DOIs
Publication statusPublished - Dec 2023

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