| Project/Area Number |
16591176
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | RIKEN |
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Principal Investigator |
YAMADA Kazuo RIKEN, Lab.for Molecular Psychiatry, Researcher, 分子精神科学研究チーム, 研究員 (10322695)
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| Co-Investigator(Kenkyū-buntansha) |
OHNISHI Tetsuo RIKEN, Lab.for Molecular Psychiatry, Researcher, 分子精神科学研究チーム, 研究員 (80373281)
YOSHIKAWA Takeo RIKEN, Lab.for Molecular Psychiatry, Laboratory Head, 分子精神科学研究チーム, チームリーダー (30249958)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | calcineurin / protein phosphatase / PPP3CC / schizophrenia / transmission disequilibrium test / association study / SNP / 染色体8p / 遺伝連鎖不平衡テスト / case-control study |
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| Research Abstract |
The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend previously reported association between the PPP3CC gene, encoding the calcineurin gamma catalytic subunit, and schizophrenia, we examined single nucleotide polymorphisms (SNPs) from 14 calcineurin-related candidate genes for genetic association using Japanese schizophrenic pedigrees. We obtained genetic evidence for association of the PPP3CC gene in Japanese schizophrenia pedigrees. This finding replicates the previous results of association for this gene in 210 ethnically diverse trios from the U.S. and 200 trios from South Africa. In addition, three other genes showed nominally significant association with schizophrenia. In a postmortem brain study, transcripts of these genes were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar patients. These findings raised a potentially important role for genes in calcineurin pathway in schizophrenia pathogenesis. Since one of these genes is an attractive candidate gene based on its functional link to dopamine, glutamate and neuregulin signaling, we extended our analysis by re-sequencing the entire genomic interval. One of these, a SNP located in intron 1, displayed the strongest evidence for disease association which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify novel and compelling susceptibility genes.
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