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
2010
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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