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
N1 - Funding Information:
This work was supported in part by research grants from the Japan Ministry of Education, Culture, Sports, Science and Technology ; the Ministry of Health, Labor and Welfare ; from the Core Research for Evolutional Science and Technology ; and from the Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation) . Dr. Ikeda is a Japan Society for the Promotion of Science postdoctoral fellow for research abroad and is additionally supported by the Uehara Memorial Foundation and the Great Britain Sasakawa Foundation. We thank Ms. M. Miyata and Ms. S. Ishihara for their technical support.
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.
KW - Expression: PDE7B
KW - pharmacogenomics
KW - risperidone
KW - schizophrenia
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U2 - 10.1016/j.biopsych.2009.08.030
DO - 10.1016/j.biopsych.2009.08.030
M3 - Article
C2 - 19850283
AN - SCOPUS:73849152123
SN - 0006-3223
VL - 67
SP - 263
EP - 269
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 3
ER -