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

• Published in: NATURE NEUROSCIENCE Vol. 23; no. 7; pp. 809 - 818
• Main Authors: Zhou, Hang, Sealock, Julia M., Sanchez-Roige, Sandra, Clarke, Toni-Kim, Levey, Daniel F., Cheng, Zhongshan, Li, Boyang, Polimanti, Renato, Kember, Rachel L., Smith, Rachel Vickers, Thygesen, Johan H., Morgan, Marsha Y., Atkinson, Stephen R., Thursz, Mark R., Nyegaard, Mette, Mattheisen, Manuel, Børglum, Anders D., Johnson, Emma C., Justice, Amy C., Palmer, Abraham A., McQuillin, Andrew, Davis, Lea K., Edenberg, Howard J., Agrawal, Arpana, Kranzler, Henry R., Gelernter, Joel
• Format: Journal Article Publication
• Language: English
• Published: New York Nature Publishing Group US 01.07.2020; Nature Publishing Group
• Subjects: 45/43; 631/208/205/2138; 692/699/476/5; Alcohol Drinking - genetics; Alcohol use; Alcoholism; Alcoholism - genetics; Alcohols; Animal Genetics and Genomics; Behavioral Sciences; Biobanks; Biological Techniques; Biology; Biomedical and Life Sciences; Biomedicine; Cognitive ability; Complications and side effects; Consortia; Datasets as Topic; Diagnosis; Drinking behavior; Drug use; Female; Genetic aspects; Genetic Predisposition to Disease; Genetic relationship; Genome-wide association studies; Genome-Wide Association Study; Genomes; Heritability; Humans; Liability; Loci; Male; Mental disorders; Mental illness; Meta-analysis; Multifactorial Inheritance; Neurobiology; Neurosciences; Phenotypes; Polygenic inheritance; Risk analysis; Risk factors; Risk taking; Substance use; Systematic review; United States
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-020-0643-5

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.