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Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1

Molecular Psychiatry volume 22, pages 346–352 (2017)Cite this article

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Abstract

Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the μ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study of usual daily methadone dose. In African-American (AA) OD subjects (n=383), we identified a genome-wide significant association between therapeutic methadone dose (mean=68.0 mg, s.d.=30.1 mg) and rs73568641 (P=2.8 × 10−8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg day−1 of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n=1027), no genome-wide significant associations with methadone dose (mean=77.8 mg, s.d.=33.9 mg) were observed. In an independent set of opioid-naive AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n=241, P=3.9 × 10−2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n=1410, genetic score P=1.3 × 10−3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction.

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Acknowledgements

We thank all the research participants in this study. Adult subject recruitment and assessment were overseen at the Yale School of Medicine and the APT Foundation by James Poling, PhD, and Aryeh Herman, PsyD; at McLean Hospital by Roger Weiss, MD; at the Medical University of South Carolina by Kathleen Brady, MD, PhD, and Raymond Anton, MD; and at the University of Pennsylvania initially by David Oslin, MD. Genotyping services were provided by the Center for Inherited Disease Research (CIDR) and the Yale University Center for Genome Analysis. Ann Marie Lacobelle, MS and Christa Robinson, AS provided excellent technical assistance; the SSADDA interviewers devoted substantial time and effort to phenotype the study sample; and Richard Sherva, PhD, Ryan Koesterer, MA, and John Farrell, PhD, at Boston University offered valuable assistance with data cleaning and management. Robert T Malison, MD, Department of Psychiatry, Yale School of Medicine, provided thoughtful suggestions during preparation of the manuscript. This study was supported by grants from the National Institutes of Health (NIH) (RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, MSTP 5T32GM007205-38, CTSA TL1 8UL1TR000142, F30 DA037665, N01-HG-65403, S10 RR19895); a Veterans Affairs VISN1 Career Development Award; the Department of Anesthesiology and Critical Care Medicine at The Children’s Hospital of Philadelphia through Children’s Anesthesia Associates, Ltd.; and by The Children’s Hospital of Philadelphia through a grant from the Institutional Development Fund to The Center for Applied Genomics. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Interdepartmental Neuroscience Program and Medical Scientist Training Program, Yale School of Medicine, New Haven, CT, USA

    A H Smith

  2. Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    A H Smith, K P Jensen, Y Nunez & J Gelernter

  3. VA CT Healthcare Center, West Haven, CT, USA

    A H Smith, K P Jensen, Y Nunez & J Gelernter

  4. Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    J Li & H Hakonarson

  5. Department of Medicine (Biomedical Genetics), School of Medicine, Boston University, Boston, MA, USA

    L A Farrer

  6. Department of Neurology, School of Medicine, Boston University, Boston, MA, USA

    L A Farrer

  7. Department of Ophthalmology, School of Medicine, Boston University, Boston, MA, USA

    L A Farrer

  8. Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA

    L A Farrer

  9. Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA

    L A Farrer

  10. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    H Hakonarson

  11. Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania and Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    S D Cook-Sather

  12. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania and Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA

    H R Kranzler

  13. Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA

    J Gelernter

  14. Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA

    J Gelernter

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Competing interests

Dr Kranzler reports being a consultant, continuing medical education (CME) speaker or advisory board member for Alkermes, Indivior, Lundbeck and Otsuka and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer and XenoPort. The other authors declare no conflict of interest.

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Smith, A., Jensen, K., Li, J. et al. Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1. Mol Psychiatry 22, 346–352 (2017). https://doi.org/10.1038/mp.2016.257

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