title: 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-1of 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.
authors.affiliation: Interdepartmental Neuroscience Program and Medical Scientist Training Program, Yale School of Medicine, New Haven, CT, USA.|Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Smith
authors.affiliation: Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Jensen
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nunez
authors.affiliation: Department of Medicine (Biomedical Genetics), School of Medicine, Boston University, Boston, MA, USA.|Department of Neurology, School of Medicine, Boston University, Boston, MA, USA.|Department of Ophthalmology, School of Medicine, Boston University, Boston, MA, USA.|Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.|Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Cook-Sather
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania and Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, West Haven, CT, USA.|Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.|Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000483:Alleles; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use; D009293:Opioid-Related Disorders / Q000235:genetics*; D010146:Pain / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D000701:Analgesics, Opioid; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D009020:Morphine; D008691:Methadone