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 from 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 single-nucleotide polymorphisms were genome-wide significant (P < 5 × 10–8) 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 and 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.
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Data availability
The MVP summary statistics were obtained via an approved dbGaP application (phs001672.v4.p1). For details on the MVP, see https://www.research.va.gov/mvp/ and ref. 76. This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration Cooperative Studies Program award G002.
Publicly available data were also downloaded from the psychiatric genomics consortium (https://www.med.unc.edu/pgc/) and the GSCAN consortium (https://conservancy.umn.edu/handle/11299/201564).
The datasets used for the BioVU analyses described were obtained from Vanderbilt University Medical Center’s biorepository, which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the National Institutes of Health-funded Shared Instrumentation grant S10RR025141; and Clinical and Translational Science Awards (CTSA) grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962 and R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/.
Data from Yale–Penn 1 are available through dbGAP accession no phs000425.v1.p1 including 1,889 African American subjects and 1,020 European-American subjects. Yale–Penn 1 data are also available through dbGAP accession no phs000952.v1.p1 including 1,531 African American subjects and 1,339 self-reported European-American subjects. Summary statistics for all Yale–Penn data are available on request to J.G. (joel.gelernter@yale.edu).
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Acknowledgements
The authors would like to thank Cold Harbor Labroatory for posting a preprint of this work on MedRxiv (https://www.medrxiv.org/). The authors thank Million Veteran Program (MVP) staff, researchers and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enroll in the study. Funding: K01 AA030083 (A.S.H.), T32 DA007261 (A.S.H.), DA54869 (A.A., J.G., H.E.), R01 DA54750 (A.A., R.B.), K02 DA32573 (A.A.), R21 AA027827 (R.B.), U01 DA055367 (R.B.), K01 DA51759 (E.C.J.), K23 MH121792 (N.R.K.), DP1 DA54394 (S.S.-R.), T32 MH014276 (G.A.P.), R01 AA027522 (A.E.), F31 AA029934 (S.E.P.), R01 MH120219 (E.M.T.-D., A.D.G.), RF1 AG073593 (E.M.T.-D., A.D.G.), P30 AG066614 (E.M.T.-D.), P2CHD042849 (E.M.T.-D.), R33 DA047527 (R.P., G.A.P.) and T32 AA028259 (J.D.D.)
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A.S.H. designed the study and conducted analyses. S.M.C.C., E.C.J., S.B.H., J.D.D., G.A.P., M.V.J., S.S.-R., S.E.P., N.R.K., I.H. and D.A.A.B. conducted various analyses. A.A., R.B., H.J.E. and J.G. supervised the study. A.D.G. and E.M.T.-D. provided statistical guidance. A.E., H.R.K., R.P., L.K.D. and S.S.-R. guided interpretation of key findings. A.S.H., H.J.E., J.G., R.B. and A.A. drafted the manuscript. A.S.H., S.M.C.C., J.D.D., M.V.J., S.E.P., N.R.K. and I.H. organized the data. The consortium members provided insight into various aspects of analyses and interpretation and data for some of the discovery GWAS that were inputs to these analyses. All named authors reviewed, edited and approved the submission.
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H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, 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. H.R.K. and J.G. hold US Patent 10900,082: ‘Genotype-guided dosing of opioid agonists’ issued on 26 January 2021. The remaining authors declare no competing interests.
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Hatoum, A.S., Colbert, S.M.C., Johnson, E.C. et al. Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders. Nat. Mental Health 1, 210–223 (2023). https://doi.org/10.1038/s44220-023-00034-y
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DOI: https://doi.org/10.1038/s44220-023-00034-y
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