Genome-wide association study identifies a potent locus associated with human opioid sensitivity

D. Nishizawa, K. Fukuda, S. Kasai, J. Hasegawa, Y. Aoki, A. Nishi, N. Saita, Y. Koukita, M. Nagashima, R. Katoh, Y. Satoh, M. Tagami, S. Higuchi, H. Ujike, N. Ozaki, T. Inada, Nakao Iwata, I. Sora, M. Iyo, N. KondoM. J. Won, N. Naruse, K. Uehara-Aoyama, M. Itokawa, M. Koga, T. Arinami, Y. Kaneko, M. Hayashida, K. Ikeda

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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.

Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalMolecular Psychiatry
Volume19
Issue number1
DOIs
Publication statusPublished - 01-01-2014

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Genome-Wide Association Study
Opioid Analgesics
Single Nucleotide Polymorphism
Substance-Related Disorders
Genetic Polymorphisms
Morphine
Analgesics
Healthy Volunteers
Alleles
Methamphetamine
Linkage Disequilibrium
Acute Pain
Fentanyl
Plastic Surgery
Reward
Cocaine
Chronic Pain
Alcoholism
Personality
Ethanol

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Nishizawa, D., Fukuda, K., Kasai, S., Hasegawa, J., Aoki, Y., Nishi, A., ... Ikeda, K. (2014). Genome-wide association study identifies a potent locus associated with human opioid sensitivity. Molecular Psychiatry, 19(1), 55-62. https://doi.org/10.1038/mp.2012.164
Nishizawa, D. ; Fukuda, K. ; Kasai, S. ; Hasegawa, J. ; Aoki, Y. ; Nishi, A. ; Saita, N. ; Koukita, Y. ; Nagashima, M. ; Katoh, R. ; Satoh, Y. ; Tagami, M. ; Higuchi, S. ; Ujike, H. ; Ozaki, N. ; Inada, T. ; Iwata, Nakao ; Sora, I. ; Iyo, M. ; Kondo, N. ; Won, M. J. ; Naruse, N. ; Uehara-Aoyama, K. ; Itokawa, M. ; Koga, M. ; Arinami, T. ; Kaneko, Y. ; Hayashida, M. ; Ikeda, K. / Genome-wide association study identifies a potent locus associated with human opioid sensitivity. In: Molecular Psychiatry. 2014 ; Vol. 19, No. 1. pp. 55-62.
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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.",
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Nishizawa, D, Fukuda, K, Kasai, S, Hasegawa, J, Aoki, Y, Nishi, A, Saita, N, Koukita, Y, Nagashima, M, Katoh, R, Satoh, Y, Tagami, M, Higuchi, S, Ujike, H, Ozaki, N, Inada, T, Iwata, N, Sora, I, Iyo, M, Kondo, N, Won, MJ, Naruse, N, Uehara-Aoyama, K, Itokawa, M, Koga, M, Arinami, T, Kaneko, Y, Hayashida, M & Ikeda, K 2014, 'Genome-wide association study identifies a potent locus associated with human opioid sensitivity', Molecular Psychiatry, vol. 19, no. 1, pp. 55-62. https://doi.org/10.1038/mp.2012.164

Genome-wide association study identifies a potent locus associated with human opioid sensitivity. / Nishizawa, D.; Fukuda, K.; Kasai, S.; Hasegawa, J.; Aoki, Y.; Nishi, A.; Saita, N.; Koukita, Y.; Nagashima, M.; Katoh, R.; Satoh, Y.; Tagami, M.; Higuchi, S.; Ujike, H.; Ozaki, N.; Inada, T.; Iwata, Nakao; Sora, I.; Iyo, M.; Kondo, N.; Won, M. J.; Naruse, N.; Uehara-Aoyama, K.; Itokawa, M.; Koga, M.; Arinami, T.; Kaneko, Y.; Hayashida, M.; Ikeda, K.

In: Molecular Psychiatry, Vol. 19, No. 1, 01.01.2014, p. 55-62.

Research output: Contribution to journalArticle

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AU - Nishizawa, D.

AU - Fukuda, K.

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AU - Hasegawa, J.

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AU - Inada, T.

AU - Iwata, Nakao

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.

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