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.
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 (p(allele) = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (p(JPN_2nd+UK) = .008, one-tailed, uncorrected) and in all combined data sets (p(all) = .0014, two-tailed, uncorrected and p(all) = .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.
MRC, Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Masashi
M
Ikeda
Yasuyuki
Y
Tomita
Akihiro
A
Mouri
Minori
M
Koga
Tomo
T
Okochi
Reiji
R
Yoshimura
Yoshio
Y
Yamanouchi
Yoko
Y
Kinoshita
Ryota
R
Hashimoto
Hywel J
HJ
Williams
Masatoshi
M
Takeda
Jun
J
Nakamura
Toshitaka
T
Nabeshima
Michael J
MJ
Owen
Michael C
MC
O'Donovan
Hiroyuki
H
Honda
Tadao
T
Arinami
Norio
N
Ozaki
Nakao
N
Iwata
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D030541:Databases, Genetic / Q000706:statistics & numerical data; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011569:Psychiatric Status Rating Scales; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*
D014150:Antipsychotic Agents; D018967:Risperidone