Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality

Hang Zhou; Julia Sealock; Sandra Sanchez‐Roige; Toni‐Kim Clarke; Daniel F. Levey; Zhongshan Cheng; Boyang Li; Renato A Polimanti; Rachel L. Kember; Rachel Vickers‐Smith; Johan H. Thygesen; Marsha Yvonne Morgan; Stephen R. Atkinson; Mark R. Thursz; Mette Nyegaard; Manuel Mattheisen; Anders Dupont Børglum; Emma C. Johnson; the VA Million Veteran Program; Amy C. Justice; Abraham A. Palmer; Andrew McQuillin; Lea Karatheodoris Davis; Howard J. Edenberg; Arpana Agrawal A; Henry R. Kranzler; Joel E. Gelernter

doi:10.1038/s41593-020-0643-5

GeneticsNature NeuroscienceMay 25, 2020

Peer-reviewed journal article

Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality

Hang Zhou iD, Julia Sealock iD, Sandra Sanchez‐Roige iD, Toni‐Kim Clarke iD, Daniel F. Levey iD, Zhongshan Cheng iD, Boyang Li iD, Renato A Polimanti iD, Rachel L. Kember iD, Rachel Vickers‐Smith iD, Johan H. Thygesen iD, Marsha Yvonne Morgan iD, Stephen R. Atkinson iD, Mark R. Thursz iD, Mette Nyegaard iD, Manuel Mattheisen iD, Anders Dupont Børglum iD, Emma C. Johnson iD, the VA Million Veteran Program, Amy C. Justice iD, Abraham A. Palmer iD, Andrew McQuillin iD, Lea Karatheodoris Davis iD, Howard J. Edenberg iD, Arpana Agrawal A iD, , Joel E. Gelernter iD

Abstract

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) 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 genomic conserved and regulatory 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 outcomes.

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