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

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.

Figure 1. Genome-wide significant association with methadone dose in opioid dependent (OD) African-Americans (AAs)

Regional association plot of the implicated locus on chromosome 6, showing a genome-wide significant association between methadone dose and single nucleotide polymorphism (SNP) rs73568641 (purple) (AA n = 383, P = 2.8 × 10⁻⁸). The gene nearest to rs73568641 is OPRM1. Each circle corresponds to a SNP, and the vertical position reflects the −log₁₀(P value) (left y-axis). Color coding depicts the degree of linkage disequilibrium (r²) between lead SNP rs73568641 and other SNPs in the region. The blue line indicates the recombination rate (right y-axis). Centimorgan (cM), megabase (Mb).

Figure 2. Methadone dose stratified by rs73568641 genotype in opioid dependent (OD) African-Americans (AAs)

Oral methadone dose is shown in milligrams (mg). Bars mark group means. Best fit line is shown in red.

Figure 3. Morphine dose stratified by rs73568641 genotype in pediatric African-American (AA) surgical patients

Intravenous moprhine dose is shown in micrograms/kilogram (μg/kg). Bars mark group means. Best fit line is shown in red.