Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.
| Title: | Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders. |
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| Authors: | 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. |
| Corporate Authors: | Substance Use Disorder Working Group of the Psychiatric Genomics Consortium |
| Source: | Nature. Mental health [Nat Ment Health] 2023 Mar; Vol. 1 (3), pp. 210-223. Date of Electronic Publication: 2023 Mar 22. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Springer Nature Country of Publication: England NLM ID: 9918486688806676 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2731-6076 (Electronic) Linking ISSN: 27316076 NLM ISO Abbreviation: Nat Ment Health Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Springer Nature, [2023]- |
| 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. |
| 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. |
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| Grant Information: | T32 AA028259 United States AA NIAAA NIH HHS; K02 DA032573 United States DA NIDA NIH HHS; R01 DA054750 United States DA NIDA NIH HHS; U01 DA055367 United States DA NIDA NIH HHS; R01 DA054869 United States DA NIDA NIH HHS; F31 AA029934 United States AA NIAAA NIH HHS; P2C HD042849 United States HD NICHD NIH HHS; R01 AA027522 United States AA NIAAA NIH HHS; K01 DA051759 United States DA NIDA NIH HHS; K01 AA030083 United States AA NIAAA NIH HHS; R24 HD042849 United States HD NICHD NIH HHS; MR/W030608/1 United Kingdom MRC_ Medical Research Council; R33 DA047527 United States DA NIDA NIH HHS; RF1 AG073593 United States AG NIA NIH HHS; R01 MH120219 United States MH NIMH NIH HHS; R21 AA027827 United States AA NIAAA NIH HHS; K23 MH121792 United States MH NIMH NIH HHS; P30 AG066614 United States AG NIA NIH HHS; T32 MH014276 United States MH NIMH NIH HHS; DP1 DA054394 United States DA NIDA NIH HHS; T32 DA007261 United States DA NIDA NIH HHS |
| Entry Date(s): | Date Created: 20230530 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10217792 |
| DOI: | 10.1038/s44220-023-00034-y |
| PMID: | 37250466 |
| Database: | MEDLINE |
Journal Article