Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1.
- Authors
- Smith, A H; Jensen, K P; Li, J; Nunez, Y; Farrer, L A; Hakonarson, H; Cook-Sather, S D; Kranzler, H R; Gelernter, J
- Year
- 2017
- Journal
- Molecular psychiatry
- PMID
- 28115739
- DOI
- 10.1038/mp.2016.257
- PMCID
- PMC5407902
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 ฮผ-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=68.0โmg, s.d.=30.1โmg) and rs73568641 (P=2.8 ร 10), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20โmgโday of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n=1027), no genome-wide significant associations with methadone dose (mean=77.8โmg, s.d.=33.9โmg) 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 ร 10). 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 ร 10). 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.
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 ร 10โ8). The gene nearest to rs73568641 is OPRM1. Each circle corresponds to a SNP, and the vertical position reflects the โlog10(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).
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.
Morphine dose stratified by rs73568641 genotype in pediatric African-American (AA) surgical patientsIntravenous moprhine dose is shown in micrograms/kilogram (ฮผg/kg). Bars mark group means. Best fit line is shown in red.
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