Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits

Hang Zhou(Yale University), Julia Sealock(Vanderbilt University Medical Center), Sandra Sanchez‐Roige(University of California San Diego), Toni-Kim Clarke(University of Edinburgh), Daniel F. Levey(Yale University), Zhongshan Cheng(Yale University), Boyang Li(Yale University), Renato Polimanti(Yale University), Rachel L. Kember(Veterans Health Administration), Rachel Vickers‐Smith(University of Louisville), Johan H. Thygesen(University College London), Marsha Y. Morgan(The Royal Free Hospital), Stephen R. Atkinson(Imperial College London), Mark Thursz(Imperial College London), Mette Nyegaard(Aarhus University), Manuel Mattheisen(Aarhus University), Anders D. Børglum(Aarhus University), Emma C. Johnson(Washington University in St. Louis), Amy C. Justice(Yale University), Abraham A. Palmer(University of California San Diego), Andrew McQuillin(University College London), Lea K. Davis(Vanderbilt University Medical Center), Howard J. Edenberg(Indiana University School of Medicine), Arpana Agrawal(Washington University in St. Louis), Henry R. Kranzler(Veterans Health Administration), Joel Gelernter(Yale University)
Nature Neuroscience
May 25, 2020
10.1038/s41593-020-0643-5
Cited by 403Open Access
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Abstract

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits. A genetic study of problematic alcohol use in 435,563 individuals, including data from the Million Veteran Program, Psychiatric Genomics Consortium and UK Biobank, found many novel risk loci and provided new insights into trait biology.

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