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Molecular analysis of schizophrenia by the integrated approach

综合方法对精神分裂症进行分子分析

基本信息

批准号：
14207103
负责人：
FUKUMAKI Yasuyuki
金额：
$ 33.95万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

1.Linkage studies : The first genome-wide scan using 417 STR markers in 130 families with affected sib-pairs revealed that ten chromosomes (1,2,3,4,5,8,9,14,17, and 20) had at least one region with a nominal p value <0.05. The second genome-wide scan using 5,861 SNPs in 236 Japanese families including 122 ones used in the first scan revealed that significant evidence of linkage of schizophrenia to 1p21.1-1p13.1 and suggestive evidence of linkage to 14q11.2, 4q11.2-q13.2 and 20p12.1-p11.2.2.Association studies : Based on the glutamatergic dysfunction hypothesis for the pathogenesis of schizophrenia, we conducted. a systematic study of associations between glutamate receptor genes and schizophrenia. We selected SNPs evenly distributed across the relevant gene regions for single marker and haplotype association studies. We found significant associations of haplotypes of GRIN2D, GRIA4, GRM3 and GRM8 with schizophrenia. Genome-wide association study using 27,000 STR markers is on the way. The second set of screening showed significant associations of 720 markers with schizophrenia. The third and fourth sets of screening followed by dense SNP typing will elucidate the susceptibility loci for schizophrenia.3.Model animal-based studies :(i)PCP is known to cause schizophrenia-like symptoms in human and animals, providing a well-suited model for schizophrenia. We screened the PCP-responsible genes by the microarray-based procedure using brain samples of PCP- administrated rats. We selected 10 genes differentially expressed at the level of more than 2.5 folds due to the PCP treatment. We are now doing association study of these genes with schizophrenia.(ii) To evaluate the involvement of GRIA4 in pathogenesis of schizophrenia, we generated GluR4 deficient mice by the homologous recombination technique. Heterozygous and homozygous mutant mice were born alive, appeared normal, and were fertile in adult. For behavioral examination, a 129/sv x C57BI/6J backcross is under way.

1.联系研究：首次全基因组扫描使用417个STR标记在130个家庭与受影响的同胞对发现，10条染色体（1，2，3，4，5，8，9，14，17，和20）至少有一个区域的名义p值<0.05。第二次全基因组扫描使用了236个日本家庭中的5，861个SNP，包括第一次扫描中使用的122个SNP，显示了精神分裂症与1p21.1-1p13.1连锁的显著证据，以及与14q11.2，4q11.2-q13.2和20p12.1-p11.2.2连锁的提示性证据。基于精神分裂症发病机制的谷氨酸能功能障碍假说，我们进行了。谷氨酸受体基因与精神分裂症之间关联的系统研究。我们选择了均匀分布在相关基因区域的单核苷酸多态性进行单标记和单倍型关联研究。我们发现GRIN 2D、GRIA 4、GRM 3和GRM 8单倍型与精神分裂症显著相关。使用27，000个STR标记的全基因组关联研究正在进行中。第二组筛选显示720个标记物与精神分裂症有显著关联。第三组和第四组筛选，然后进行密集SNP分型，将阐明精神分裂症的易感基因位点。3.基于动物模型的研究：（i）已知PCP在人类和动物中引起精神分裂症样症状，为精神分裂症提供了非常适合的模型。我们使用PCP给药大鼠的脑样本，通过基于微阵列的程序筛选PCP相关基因。我们选择了10个基因差异表达的水平超过2.5倍，由于PCP处理。我们现在正在做这些基因与精神分裂症的关联研究。(ii)为了评估GRIA 4在精神分裂症发病机制中的作用，我们通过同源重组技术产生GluR 4缺陷小鼠。杂合子和纯合子突变小鼠出生时存活，表现正常，成年后具有生育能力。对于行为检查，129/sv x C57 BI/6 J回交正在进行中。