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

Nature Neuroscience volume 25, pages 1279–1287 (2022)Cite this article

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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.

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Fig. 1: Manhattan and quantile–quantile plot for cross-ancestry meta-analysis of opioid use disorder (Ncases = 31,480 and Ncontrols = 394,484).
Fig. 2: Enrichment of opioid use disorder in the brain.
Fig. 3: Phenotypic spectrum associated with opioid use disorder.
Fig. 4: Genomic SEM analysis of OUD with other substance use traits and psychiatric disorders.

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Data availability

The full summary-level association data from the meta-analysis are available through dbGaP at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.

Code availability

Imputation was performed using Minimac3 (https://genome.sph.umich.edu/wiki/Minimac3). GWAS was performed using PLINK2 (https://www.cog-genomics.org/plink2). Meta-analyses were performed using METAL (https://genome.sph.umich.edu/wiki/METAL_Documentation). GCTA (https://cnsgenomics.com/software/gcta/#Overview) was used for identification of independent loci (GCTA-COJO) and gene-based analysis (GCTA-fastBAT). FUMA (https://fuma.ctglab.nl/) was used for gene association, functional enrichment and gene-set enrichment analyses. Transcriptomic analyses were performed using S-PrediXcan and S-MultiXcan (https://github.com/hakyimlab/MetaXcan). LDSC (https://github.com/bulik/ldsc) was used for heritability estimation, genetic correlation analysis (also using the CTG-VL; https://genoma.io) and heritability enrichment analyses. Trans-ancestry genetic correlation was estimated using Popcorn (https://github.com/brielin/Popcorn). PRS analyses were performed using PRS-CS (https://github.com/getian107/PRScs). PheWAS analyses were run using the PheWAS R package (https://github.com/PheWAS/PheWAS). The MendelianRandomization R package (https://cran.r-project.org/web/packages/MendelianRandomization/index.html) was used for MR analyses. Genomic SEM was conducted using the GenomicsSEM R package (https://github.com/GenomicSEM/GenomicSEM).

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Acknowledgements

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.

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  1. A list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Mental Illness Research, Education and Clinical Center, Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA

    Rachel L. Kember, Rachel Vickers-Smith, Emily E. Hartwell, Richard C. Crist, Kyle M. Kampman & Henry R. Kranzler

  2. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Rachel L. Kember, Heng Xu, Sylvanus Toikumo, Emily E. Hartwell, Richard C. Crist, Kyle M. Kampman & Henry R. Kranzler

  3. Department of Epidemiology, University of Kentucky College of Public Health, Lexington, KY, USA

    Rachel Vickers-Smith

  4. Center on Drug and Alcohol Research, Department of Behavioral Science, University of Kentucky College of Medicine, Lexington, KY, USA

    Rachel Vickers-Smith

  5. Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Maria Niarchou, Lea K. Davis & Sandra Sanchez-Roige

  6. Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA

    Hang Zhou, Christopher T. Rentsch, Amy C. Justice & Joel Gelernter

  7. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Hang Zhou, Christopher T. Rentsch, Amy C. Justice & Joel Gelernter

  8. Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK

    Christopher T. Rentsch

  9. Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA

    Amy C. Justice

  10. Department of Psychiatry, University of California, San Diego, San Diego, CA, USA

    Sandra Sanchez-Roige

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Contributions

R.L.K., H.X. and H.R.K. conceived analyses. R.L.K. and H.R.K. wrote the first draft and prepared all drafts for submission; R.L.K. accomplished primary analyses; H.X., S.T., M.N. and H.Z. conducted additional analyses; R.L.K., L.K.D., S.S.-R. and J.G. supervised additional analyses; R.V.-S., E.E.H., C.T.R., M.N., L.K.D. and S.S.-R. provided critical support regarding phenotypes and data in individual datasets; and K.M.K., A.C.J. and H.R.K. provided resource support. All authors reviewed the manuscript and approved it for submission.

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Correspondence to Henry R. Kranzler.

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Competing interests

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.

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Kember, R.L., Vickers-Smith, R., Xu, H. et al. Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction. Nat Neurosci 25, 1279–1287 (2022). https://doi.org/10.1038/s41593-022-01160-z

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