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 language | English |
|---|---|
| Pages (from-to) | 263-269 |
| Number of pages | 7 |
| Journal | Biological Psychiatry |
| Volume | 67 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 01-02-2010 |
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All Science Journal Classification (ASJC) codes
- Biological Psychiatry
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=73849152123&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73849152123&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2009.08.030
DO - 10.1016/j.biopsych.2009.08.030
M3 - Article
C2 - 19850283
AN - SCOPUS:73849152123
VL - 67
SP - 263
EP - 269
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 3
ER -