Investigation on candidate genes involved in pathophysiology of schizophrenia

精神分裂症病理生理相关候选基因的研究

• 批准号: 16390330
• 负责人: ITOKAWA Masanari
• 金额: $ 7.36万
• 依托单位: Tokyo Institute of Psychiatry
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390330/
• 关键词: polymorphism; schizophrenia; hypoglutamatergic hypothesis; case-control study; linkege disequillibrium; association study; GFAP; Reelin; VGLUT1; 2; Reelin; de novo均衡転座; DISC2; DISC1; RT-PCR; 神経発達異常仮説; 対立遺伝子頻度; HNK-1ST

We performed case-control association study for VGLUT1/2 gene based upon the hypoglutamatergic hypothesis of schizophrenia. A LD block was detected in VGLUT1 gene region and haplotype analysis showed nominally significant association (P=0.06). IVS2+87A>G displayed significant association with paranoid type schizophrenia (P=0.01). Two LD blocks were detected in VGLUT2 gene region but haplytype frequencies showed no significant different between cases and controls. IVS2-49G>A was significantly associated with female schizophrenia (P=0.02). Those associations were not significant after Bonfferoni's correction.Several lines of evidence support idea that functional disturbance of GFAP is involved in development of schizophrenia. We therefore investigated GFAP gene and 3 SNPs were significantly associated with schizophrenia (P<0.01). The data suggested that dysfunction of neuron-glia interaction could play a role in vulnerability of schizophrenia.We detected positive association between Reelin gene and schizophrenia last year. SNPs which showed significant association could be related to splicing variations since they were located near intron/exon boundary. We performed RT-PCR for the exons of Reelin near the SNPs and detected novel spliced variant skipping exon9. Real-time PCR revealed mRNA skipping exon9 was elevated in schizophrenia compared to control brains.

基于精神分裂症的低血糖假说，我们对VGLUT 1/2基因进行了病例对照关联研究。在VGLUT 1基因区域检测到LD阻断，单倍型分析显示名义上显著的关联（P=0.06）。IVS 2 + 87 A>G与偏执型精神分裂症有显著相关性（P=0.01）。在VGLUT 2基因区检测到两个LD阻断，但病例组和对照组之间的等位基因型频率无显著差异。IVS 2 - 49 G>A与女性精神分裂症的发生有显著相关性（P=0.02）。这些关联在Bonfferoni修正后并不显著。几条证据支持GFAP功能障碍参与精神分裂症的发展的观点。因此，我们研究了GFAP基因，发现3个SNPs与精神分裂症有显著相关性（P<0.01）。这些数据表明神经元-胶质细胞相互作用的障碍可能在精神分裂症的易感性中起作用。显示显著关联的SNPs可能与剪接变异有关，因为它们位于内含子/外显子边界附近。我们对Reelin基因外显子的SNPs附近进行了RT-PCR，并检测到了新的剪接变异体跳跃外显子9。实时PCR显示，与对照组相比，精神分裂症患者的mRNA跳跃外显子9升高。

项目成果

Japanese Schizophrenia Sib-Pair Linkage Group. Genome-wide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p,14q,and 20p.

日本精神分裂症同胞配对连锁小组。

• 发表时间: 2005
• 期刊: Am.J.Hum.Genet. 77
• 作者: Yamada K;Ohnishi T;Hashimoto K;Ohba H;Iwayama-Shigeno Y;Toyoshima M;Okuno A;Takao H;Toyota T;Minabe Y;Nakamura K;Shimizu E;Itokawa M;Mori N;Ito M;Yoshikawa T.;Itokawa M. (51)
• 通讯作者: Itokawa M. (51)

A 200-kb region of human chromosome 22q11 confers schizophrenia-related behavioral abnormalities in mice.

人类染色体 22q11 的 200 kb 区域导致小鼠出现与精神分裂症相关的行为异常。

• 发表时间: 2005
• 期刊: Proc Natl Acad Sci USA. 102
• 作者: Hiroi N;Zhu H;Lee MS;Funke B;Sawamura T;Arai M;Itokawa M;Kucherlapati R;Morrow B;Agatsuma S.
• 通讯作者: Agatsuma S.

dentification of Multiple mRNA isoforms of Serine Racemase and Genetic Analysis in Schizophrenia and D-Serine Levels

丝氨酸消旋酶多种 mRNA 亚型的鉴定以及精神分裂症和 D-丝氨酸水平的遗传分析

• 发表时间: 2005
• 期刊: Biol.Psychiat (in press)
• 作者: Yamada;K.;Ohnishi;t.;Hashimoto;K.;et al.
• 通讯作者: et al.

A 200-kb region of human chromosome 22q11confers schizophrenia-related behavioral abnormalities in mice

人类染色体 22q11 的 200 kb 区域赋予小鼠精神分裂症相关的行为异常

• 发表时间: 2005
• 期刊: Proc Natl Acad Sci USA. 102
• 作者: Hiroi N;Zhu H;Lee MS;Funke B;Sawamura T;Arai M;Itokawa M;Kucherlapati R;Morrow B;Agatsuma S.
• 通讯作者: Agatsuma S.

A polymorphism in the PDLIM5 gene associated with gene expression and schizophrenia

• DOI: 10.1016/j.biopsych.2005.07.041
• 发表时间: 2006-03-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Horiuchi, Y;Arai, M;Arinami, T
• 通讯作者: Arinami, T