Format

Send to

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

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

Author information

1
Interdepartmental Neuroscience Program and Medical Scientist Training Program, Yale School of Medicine, New Haven, CT, USA.
2
Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
3
VA CT Healthcare Center, West Haven, CT, USA.
4
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5
Department of Medicine (Biomedical Genetics), School of Medicine, Boston University, Boston, MA, USA.
6
Department of Neurology, School of Medicine, Boston University, Boston, MA, USA.
7
Department of Ophthalmology, School of Medicine, Boston University, Boston, MA, USA.
8
Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
9
Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA.
10
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
11
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA, USA.
12
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania and Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA.
13
Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
14
Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.

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.

PMID:
28115739
PMCID:
PMC5407902
DOI:
10.1038/mp.2016.257
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center