Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality
Rachel L. Kember,
Rachel Vickers Smith,
Johan H. Thygesen,
Marsha Y. Morgan,
Stephen R. Atkinson,
Mark R. Thursz,
Anders D Børglum,
Emma C. Johnson,
the VA Million Veteran Program,
Amy C. Justice,
Abraham A Palmer,
Lea K. Davis,
Howard J. Edenberg,
Henry R. Kranzler,
Posted 16 Aug 2019
bioRxiv DOI: 10.1101/738088 (published DOI: 10.1038/s41593-020-0643-5)
Posted 16 Aug 2019
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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