title: Genome-wide association study identifies a potent locus associated with human opioid sensitivity.
abstract: Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Nishizawa
authors.affiliation: Division of Dental Anesthesiology, Department of Oral Health and Clinical Science, Orofacial Pain Center Suidoubashi Hospital, Tokyo Dental College, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kasai
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Hasegawa
authors.affiliation: 1] Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2] Division of Dental Anesthesiology, Department of Oral Health and Clinical Science, Orofacial Pain Center Suidoubashi Hospital, Tokyo Dental College, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Division of Dental Anesthesiology, Department of Oral Health and Clinical Science, Orofacial Pain Center Suidoubashi Hospital, Tokyo Dental College, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Saita
authors.affiliation: Division of Dental Anesthesiology, Department of Oral Health and Clinical Science, Orofacial Pain Center Suidoubashi Hospital, Tokyo Dental College, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Koukita
authors.affiliation: Department of Surgery, Toho University Sakura Medical Center, Sakura, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nagashima
authors.affiliation: Department of Surgery, Toho University Sakura Medical Center, Sakura, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Katoh
authors.affiliation: Department of Anesthesiology, Toho University Sakura Medical Center, Sakura, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Anesthesiology, Toho University Sakura Medical Center, Sakura, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tagami
authors.affiliation: National Hospital Organization, Kurihama Alcoholism Center, Yokosuka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
authors.affiliation: Ujike Nishiguchi Clinic, Okayama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ujike
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Psychiatry, Seiwa Hospital, Institute of Neuropsychiatry, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inada
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Iwata
authors.affiliation: 1] Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2] Department of Psychobiology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Sora
authors.affiliation: Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Iyo
authors.affiliation: Seimei Hospital, Fuji City, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Koujin Hospital, Nagoya, Japan.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Won
authors.affiliation: Saitama Seishin-iryo Center, Kita-adachi, Saitama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Naruse
authors.affiliation: Kanagawa-Kenritsu Seisin Iryo Senta Serigaya Byoin, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Uehara-Aoyama
authors.affiliation: Schizophrenia and Depression Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Itokawa
authors.affiliation: Departrnent of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Koga
authors.affiliation: Departrnent of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Arinami
authors.affiliation: Division of Dental Anesthesiology, Department of Oral Health and Clinical Science, Orofacial Pain Center Suidoubashi Hospital, Tokyo Dental College, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Anesthesiology & Pain Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hayashida
authors.affiliation: Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D019651:Plastic Surgery Procedures / Q000009:adverse effects; D019966:Substance-Related Disorders / Q000235:genetics; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D015254:DNA Modification Methylases; C585168:METTL21A protein, human