Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.

Autor: Hatoum AS; Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA., Colbert SMC; Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA., Johnson EC; Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA., Huggett SB; Emory University, Department of Psychology., Deak JD; Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA., Pathak G; Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, USA., Jennings MV; UC San Diego School of Medicine, Department of Psychiatry, San Diego, CA, USA., Paul SE; Department of Psychological & Brain Sciences, Washington University in St. Louis., Karcher NR; Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA., Hansen I; Department of Psychological & Brain Sciences, Washington University in St. Louis., Baranger DAA; Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA., Edwards A; Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA., Grotzinger A; University of Colorado-Boulder, Institute for Behavioral Genetics, Boulder, CO, USA., Tucker-Drob EM; University of Texas at Austin, Department of Psychology and Population Research Center, Austin, TX, USA., Kranzler HR; Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA., Davis LK; Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA., Sanchez-Roige S; UC San Diego School of Medicine, Department of Psychiatry, San Diego, CA, USA.; Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA., Polimanti R; Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA., Gelernter J; Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, USA.; University of Texas at Austin, Department of Psychology and Population Research Center, Austin, TX, USA.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA., Edenberg HJ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Bogdan R; Department of Psychological & Brain Sciences, Washington University in St. Louis., Agrawal A; Washington University School of Medicine, Department of Psychiatry, Saint Louis, USA.
Jazyk: angličtina
Zdroj: Nature. Mental health [Nat Ment Health] 2023 Mar; Vol. 1 (3), pp. 210-223. Date of Electronic Publication: 2023 Mar 22.
DOI: 10.1038/s44220-023-00034-y
Abstrakt: 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.
Competing Interests: Disclosure: Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals and Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. Drs. Kranzler and Gelernter hold U..S. Patent 10900,082: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. The remaining authors declare not conflicts of interest.
Databáze: MEDLINE
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