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

Mol Psychiatry. 2017 Mar;22(3):346-352. doi: 10.1038/mp.2016.257. Epub 2017 Jan 24.


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.

MeSH terms

  • Adult
  • Alleles
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology*
  • Analgesics, Opioid / therapeutic use
  • Black or African American / genetics
  • Dose-Response Relationship, Drug
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Genotype
  • Humans
  • Male
  • Methadone / therapeutic use
  • Middle Aged
  • Morphine / therapeutic use
  • Opioid-Related Disorders / genetics*
  • Pain / drug therapy
  • Pain / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Opioid, mu / genetics
  • United States
  • White People / genetics


  • Analgesics, Opioid
  • OPRM1 protein, human
  • Receptors, Opioid, mu
  • Morphine
  • Methadone