Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

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Abstract

Despite an estimated heritability of ~50%, genome-wide association studies of opioid use disorder (OUD) have revealed few genome-wide significant loci. We conducted a cross-ancestry meta-analysis of OUD in the Million Veteran Program (N = 425,944). In addition to known exonic variants in OPRM1 and FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1 and KCNN1. A meta-analysis including other datasets identified a locus in TSNARE1. In total, we identified 14 loci for OUD, 12 of which are novel. Significant genetic correlations were identified for 127 traits, including psychiatric disorders and other substance use-related traits. The only significantly enriched cell-type group was CNS, with gene expression enrichment in brain regions previously associated with substance use disorders. These findings increase our understanding of the biological basis of OUD and provide further evidence that it is a brain disease, which may help to reduce stigma and inform efforts to address the opioid epidemic.

Original languageEnglish
Pages (from-to)1279-1287
Number of pages9
JournalNature Neuroscience
Volume25
Issue number10
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This work was supported by Merit Review Awards from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service (no. I01 BX003341 (to A.C.J. and H.R.K.)) and Clinical Science Research and Development Service (no. I01 CX001734 (to K.M.K.)); the VISN 4 Mental Illness Research, Education and Clinical Center (to H.R.K.); NIAAA grant K01 AA028292 (to R.L.K.); and NIDA grant DA046345 (to H.R.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the position or policy of the Department of Veterans Affairs or the US Government.

Funding Information:
H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes, 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. J.G. and H.R.K. are holders of US patent no. 10,900,082 titled: ‘Genotype-guided dosing of opioid agonists,’ issued 26 January 2021. The other authors declare no competing interests.

Funding Information:
This work was supported by Merit Review Awards from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service (no. I01 BX003341 (to A.C.J. and H.R.K.)) and Clinical Science Research and Development Service (no. I01 CX001734 (to K.M.K.)); the VISN 4 Mental Illness Research, Education and Clinical Center (to H.R.K.); NIAAA grant K01 AA028292 (to R.L.K.); and NIDA grant DA046345 (to H.R.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the position or policy of the Department of Veterans Affairs or the US Government.

Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

ASJC Scopus subject areas

  • Neuroscience (all)

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