TY - JOUR
T1 - Genome-wide association study identifies a potent locus associated with human opioid sensitivity
AU - Nishizawa, D.
AU - Fukuda, K.
AU - Kasai, S.
AU - Hasegawa, J.
AU - Aoki, Y.
AU - Nishi, A.
AU - Saita, N.
AU - Koukita, Y.
AU - Nagashima, M.
AU - Katoh, R.
AU - Satoh, Y.
AU - Tagami, M.
AU - Higuchi, S.
AU - Ujike, H.
AU - Ozaki, N.
AU - Inada, T.
AU - Iwata, N.
AU - Sora, I.
AU - Iyo, M.
AU - Kondo, N.
AU - Won, M. J.
AU - Naruse, N.
AU - Uehara-Aoyama, K.
AU - Itokawa, M.
AU - Koga, M.
AU - Arinami, T.
AU - Kaneko, Y.
AU - Hayashida, M.
AU - Ikeda, K.
N1 - Funding Information:
We acknowledge Dr Keiji Tanaka for critically reading the manuscript and Mr Michael Arends for his assistance with editing the manuscript. We are grateful to the volunteers for their participation in this study and the anesthesiologists, surgeons and psychiatrists at related hospitals for collecting clinical data. We thank the Stanley Medical Research Institute Brain Collection for donating specimens. This work was supported by grants from the MEXT of Japan (20390162, 23390377), MHLW of Japan (H21-3jigan-ippan-011, H22-Iyaku -015) and Smoking Research Foundation.
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
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U2 - 10.1038/mp.2012.164
DO - 10.1038/mp.2012.164
M3 - Article
C2 - 23183491
AN - SCOPUS:84891166214
SN - 1359-4184
VL - 19
SP - 55
EP - 62
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 1
ER -
