학술논문
Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders
Document Type
article
Author
Hatoum, Alexander S; Colbert, Sarah MC; Johnson, Emma C; Huggett, Spencer B; Deak, Joseph D; Pathak, Gita A; Jennings, Mariela V; Paul, Sarah E; Karcher, Nicole R; Hansen, Isabella; Baranger, David AA; Edwards, Alexis; Grotzinger, Andrew D; Tucker-Drob, Elliot M; Kranzler, Henry R; Davis, Lea K; Sanchez-Roige, Sandra; Polimanti, Renato; Gelernter, Joel; Edenberg, Howard J; Bogdan, Ryan; Agrawal, Arpana
Source
Nature Mental Health. 1(3)
Subject
Language
Abstract
Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.