Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia: Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches

Masashi Ikeda, Yasuyuki Tomita, Akihiro Mouri, Minori Koga, Tomo Okochi, Reiji Yoshimura, Yoshio Yamanouchi, Yoko Kinoshita, Ryota Hashimoto, Hywel J. Williams, Masatoshi Takeda, Jun Nakamura, Toshitaka Nabeshima, Michael J. Owen, Michael C. O'Donovan, Hiroyuki Honda, Tadao Arinami, Norio Ozaki, Nakao Iwata

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Abstract

Background: Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response. Methods: To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex. Results: Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (pallele = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (pJPN_2nd+UK = .008, one-tailed, uncorrected) and in all combined data sets (pall = .0014, two-tailed, uncorrected and pall = .018, two-tailed, Bonferroni correction). Conclusions: We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches.

Original languageEnglish
Pages (from-to)263-269
Number of pages7
JournalBiological Psychiatry
Volume67
Issue number3
DOIs
Publication statusPublished - 01-02-2010

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Risperidone
Genetic Association Studies
Schizophrenia
Single Nucleotide Polymorphism
Genes
Pharmacogenetics
Prefrontal Cortex
Transcriptome
Pharmacogenomic Testing
Messenger RNA
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Ikeda, Masashi ; Tomita, Yasuyuki ; Mouri, Akihiro ; Koga, Minori ; Okochi, Tomo ; Yoshimura, Reiji ; Yamanouchi, Yoshio ; Kinoshita, Yoko ; Hashimoto, Ryota ; Williams, Hywel J. ; Takeda, Masatoshi ; Nakamura, Jun ; Nabeshima, Toshitaka ; Owen, Michael J. ; O'Donovan, Michael C. ; Honda, Hiroyuki ; Arinami, Tadao ; Ozaki, Norio ; Iwata, Nakao. / Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia : Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches. In: Biological Psychiatry. 2010 ; Vol. 67, No. 3. pp. 263-269.
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abstract = "Background: Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response. Methods: To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex. Results: Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (pallele = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (pJPN_2nd+UK = .008, one-tailed, uncorrected) and in all combined data sets (pall = .0014, two-tailed, uncorrected and pall = .018, two-tailed, Bonferroni correction). Conclusions: We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches.",
author = "Masashi Ikeda and Yasuyuki Tomita and Akihiro Mouri and Minori Koga and Tomo Okochi and Reiji Yoshimura and Yoshio Yamanouchi and Yoko Kinoshita and Ryota Hashimoto and Williams, {Hywel J.} and Masatoshi Takeda and Jun Nakamura and Toshitaka Nabeshima and Owen, {Michael J.} and O'Donovan, {Michael C.} and Hiroyuki Honda and Tadao Arinami and Norio Ozaki and Nakao Iwata",
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Ikeda, M, Tomita, Y, Mouri, A, Koga, M, Okochi, T, Yoshimura, R, Yamanouchi, Y, Kinoshita, Y, Hashimoto, R, Williams, HJ, Takeda, M, Nakamura, J, Nabeshima, T, Owen, MJ, O'Donovan, MC, Honda, H, Arinami, T, Ozaki, N & Iwata, N 2010, 'Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia: Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches', Biological Psychiatry, vol. 67, no. 3, pp. 263-269. https://doi.org/10.1016/j.biopsych.2009.08.030

Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia : Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches. / Ikeda, Masashi; Tomita, Yasuyuki; Mouri, Akihiro; Koga, Minori; Okochi, Tomo; Yoshimura, Reiji; Yamanouchi, Yoshio; Kinoshita, Yoko; Hashimoto, Ryota; Williams, Hywel J.; Takeda, Masatoshi; Nakamura, Jun; Nabeshima, Toshitaka; Owen, Michael J.; O'Donovan, Michael C.; Honda, Hiroyuki; Arinami, Tadao; Ozaki, Norio; Iwata, Nakao.

In: Biological Psychiatry, Vol. 67, No. 3, 01.02.2010, p. 263-269.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia

T2 - Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches

AU - Ikeda, Masashi

AU - Tomita, Yasuyuki

AU - Mouri, Akihiro

AU - Koga, Minori

AU - Okochi, Tomo

AU - Yoshimura, Reiji

AU - Yamanouchi, Yoshio

AU - Kinoshita, Yoko

AU - Hashimoto, Ryota

AU - Williams, Hywel J.

AU - Takeda, Masatoshi

AU - Nakamura, Jun

AU - Nabeshima, Toshitaka

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Honda, Hiroyuki

AU - Arinami, Tadao

AU - Ozaki, Norio

AU - Iwata, Nakao

PY - 2010/2/1

Y1 - 2010/2/1

N2 - Background: Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response. Methods: To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex. Results: Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (pallele = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (pJPN_2nd+UK = .008, one-tailed, uncorrected) and in all combined data sets (pall = .0014, two-tailed, uncorrected and pall = .018, two-tailed, Bonferroni correction). Conclusions: We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches.

AB - Background: Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response. Methods: To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex. Results: Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (pallele = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (pJPN_2nd+UK = .008, one-tailed, uncorrected) and in all combined data sets (pall = .0014, two-tailed, uncorrected and pall = .018, two-tailed, Bonferroni correction). Conclusions: We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches.

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