| 1 | Biol. Psychiatry 2010 Feb 67: 263-9 |
|---|---|
| PMID | 19850283 |
| Title | 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. |
| Abstract | 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. 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. 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). 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Biol. Psychiatry 2010 Feb 67: 263-9 |
| PMID | 19850283 |
| Title | 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. |
| Abstract | 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. 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. 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). 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Eur. J. Neurosci. 2013 Sep 38: 2853-63 |
| PMID | 23738838 |
| Title | unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model. |
| Abstract | DCC and UNC5 homologs (UNC5H) are guidance cue receptors highly expressed by mesocorticolimbic dopamine neurons. We have shown that dcc heterozygous mice exhibit increased dopamine, but not norepinephrine, innervation and function in medial prefrontal cortex. Concomitantly, dcc heterozygotes show blunted mesolimbic dopamine release and behavioral responses to stimulant drugs. These changes appear only in adulthood. Recently, we found an adolescent emergence of UNC5H expression by dopamine neurons and co-expression of DCC and UNC5H by single dopamine cells. Here, we demonstrate selective expression of unc5 homolog c mRNA by dopamine neurons in adulthood. We show that UNC5C haploinsufficiency results in diminished amphetamine-induced locomotion in male and female mice. This phenotype is identical to that produced by dcc haploinsufficiency and is observed after adolescence. Notably, and similar to dcc haploinsufficiency, UNC5C haploinsufficiency leads to dramatic increases in tyrosine hydroxylase expression in the medial prefrontal cortex, but not in the nucleus accumbens. In contrast, medial prefrontal cortex dopamine-?-hydroxylase expression is not altered. We confirmed that UNC5C protein is reduced in the ventral tegmental area of UNC5C heterozygous mice, but that DCC expression in this region remains unchanged. UNC5C receptors may also play a role in dopamine function and influence sensitivity to behavioral effects of stimulant drugs of abuse, at least upon first exposure. The striking similarities between the dcc and the UNC5C haploinsufficient phenotypes raise the possibility that functions mediated by DCC/UNC5C complexes may be at play. |
| SCZ Keywords | schizophrenia, schizophrenic |