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Study on susceptibly genes for schizophrenia and tubercubsis

精神分裂症和结核病易感基因的研究

基本信息

批准号：
12204009
负责人：
FUKUMAKI Yasuyuki
金额：
$ 45.63万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

1. Study on schizophrenia susceptibilityThe 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.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 region for typing and did single marker and haplotype association studies. We found significant associations of halotypes 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.2. Study on tuberculosis susceptibilityWe performed a gene-based association analysis of 21 candidate genes on 87 TB patients and 265 controls using 118 marker single nucleotide polymorphisms (SNPs). Subsequently, we analyzed the association between TB and coding SNPs (cSNPs) adjacent to positive marker SNPs. Three cSNPs of 1L.12RB1 were significantly associated with the development of TB, suggesting that 1L_12RB1 confers genetic susceptibility to TB in Japanese. We also collected blood samples from 56 patients who showed susceptibility to mycobacterial infection, and identified partial dominant IFN-y receptor 1 deficiency in 3 unrelated patients with BCG osteomyelitis and in one of their fathers. This is the first report of this disorder in Japanese.

1.精神分裂症易感性研究首次对130个家系的417个STR位点进行全基因组扫描，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，其中包括第一次扫描中使用的122个SNP，结果显示，精神分裂症与1p21.1-1p13.1连锁的显著证据和与14q11.2连锁的暗示性证据，4q11.2-q13.2和20p12.1-p11.2。本研究基于谷氨酸能功能障碍假说，对谷氨酸受体基因与精神分裂症的关系进行了系统研究。我们选择了均匀分布在相关基因区域的SNP进行分型，并进行了单标记和单倍型关联研究。我们发现GRIN 2D、GRIA 4、GRM 3和GRM 8的晕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。第三和第四组筛选后的密集SNP分型将阐明精神分裂症的易感基因位点。结核病易感性研究我们用118个单核苷酸多态性（SNP）标记对87例结核病患者和265名对照者的21个候选基因进行了基于基因的关联分析。随后，我们分析了结核病与邻近阳性标记SNP的编码SNP（cSNP）之间的关联。1L_12RB1的三个cSNPs与TB的发展显著相关，表明1L_12RB1赋予日本人对TB的遗传易感性。我们还收集了56例对分枝杆菌感染敏感的患者的血液样本，并在3例不相关的BCG骨髓炎患者及其父亲中发现了部分显性IFN-γ受体1缺乏症。这是日本首次报道这种疾病。