Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders
Hatoum, A. S.; Colbert, S. M. C.; Johnson, E. C.; Huggett, S. B.; Deak, J. D.; Pathak, G. A.; Jennings, M. V.; Paul, S. E.; Karcher, N. R.; Hansen, I.; Baranger, D. A. A.; Edwards, A.; Grotzinger, A. D.; Substance Use Disorder Working Group of the Psychiatric Genomics Consortium, ; Tucker-Drob, E. M.; Kranzler, H.; Davis, L. K.; Sanchez-Roige, S.; Polimanti, R.; Gelernter, J.; Edenberg, H. J.; Bogdan, R.; Agrawal, A.
Show abstract
Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates general and substance-specific loci for problematic alcohol use, problematic tobacco use, and cannabis and opioid use disorders in a sample of 1,025,550 individuals of European and 92,630 individuals of African descent. Nineteen loci were genome-wide significant for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries PDE4B was significant (among others), suggesting dopamine regulation as a cross-trait vulnerability. The 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 the genetic architecture of general and substance-specific use disorder risk that may be leveraged as treatment targets.
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