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.

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

“…Another GWAS study reported that the C allele of rs2952768 in the Chr2q33.3 was associated with more analgesic requirements in human (Nishizawa et al., 2014). Multiple GWAS studies have proposed genes ( PRDM16 , TRPM8 or LRP1 ) and locus (Chr8q22.1) to be involved in the migraine (Anttila et al, 2010; Chasman et al., 2011).…”

Association Between KCNJ6 (GIRK2) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence

“…For the analysis of personality profile data from healthy volunteer subjects, raw TCI scores were processed according to a previous report (33). The score on each subscale in each dimension was averaged, in which the total score was divided by the number of items in each subscale.…”

“…The TCI used in the present study was based on the shortened 125-item questionnaire of the longer 240-item Japanese version of the TCI. The usage of the TCI for the analysis in the present study is detailed in the Supplementary Materials and Methods and a previous report (33).…”

“…For the subjects who underwent cosmetic orthognathic surgery, the surgical protocol and subsequent postoperative pain management were fundamentally the same as those of the previous study (33,38) and detailed in the Supplementary Materials and Methods. Postoperative patient-controlled analgesia (PCA) fentanyl use during the first 24-h postoperative period was recorded.…”

“…Enrolled in the initial analysis to explore the association between GIRK2 gene polymorphisms and the sensitivity to opioid-induced analgesia were 355 healthy patients who were scheduled to undergo cosmetic orthognathic surgery (mandibular sagittal split ramus osteotomy) for mandibular prognathism at Tokyo Dental College Suidoubashi Hospital, as described in the Supplementary Materials and Methods (available in the online version only) and a previous report (33). Peripheral blood samples were collected from these subjects for the gene analysis.…”