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

• Published in: Molecular psychiatry Vol. 22; no. 3; pp. 346 - 352
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2017; Nature Publishing Group
• Subjects: 692/53/2423; Addictions; Adult; African Americans; Alleles; Analgesics; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Analgesics, Opioid - therapeutic use; Behavioral Sciences; Biological Psychology; Black or African American - genetics; Dosage; Dose-response relationship; Dose-Response Relationship, Drug; Drug dependence; Drug dosages; Drug therapy; Female; Gene Frequency; Gene loci; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic variation; Genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genotype; Health aspects; Humans; immediate-communication; Male; Medicine; Medicine & Public Health; Methadone; Methadone - therapeutic use; Middle Aged; Morphine; Morphine - therapeutic use; Narcotics; Neurosciences; Opioid receptors; Opioid-Related Disorders - genetics; Opium habit; Pain; Pain - drug therapy; Pain - genetics; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Psychiatry; Public health; Receptors, Opioid, mu - genetics; Risk factors; United States; White People - genetics; United States; United States > US
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2016.257

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.