Identification of susceptibility genes for sporadic Parkinson's disease by genotyping multiple SNPs

通过对多个 SNP 进行基因分型鉴定散发性帕金森病的易感基因

基本信息

批准号：
17590874
负责人：
MIZUTA Ikuko
金额：
$ 1.92万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590874/
关键词：
Parkinson's disease single nucleotide polymorphism susceptibility gene association study

项目摘要

Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder, with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case-control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case-control populations, we found that a SNP in α-synuclein (SNCA), rs7684318,showed the strongest association with PD (P=5.0x10^<-10>). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D'>0.9) spanning about 120 kb. A tight LD group (r^2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0x10^<-9>-1.7x10^<-11>). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated to the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.

帕金森病 (PD) 是最常见的人类神经退行性疾病之一，其特征是中脑黑质中的多巴胺能神经元丧失，PD 是一种复杂的疾病，具有影响疾病风险的多种遗传和环境因素。对于散发性帕金森病，我们对两个独立的病例对照人群中的 121 个候选基因的 268 个单核苷酸多态性 (SNP) 进行了病例对照关联研究，发现其中的一个 SNP。 α-突触核蛋白 (SNCA)，rs7684318，显示出与 PD 的最强相关性 (P=5.0x10^<-10>)，使用 rs7684318 周围区域的 29 个 SNP 进行连锁不平衡 (LD) 分析，结果显示整个 SNCA 基因位于单个 LD 块 (D'>0.9) 跨越约 120 kb 紧密的 LD 组。 (r^2>0.85) 的 6 个 SNP（包括 rs7684318）与 PD 相关性最强（P=2.0x10^<-9>-1.7x10^<-11>）。单倍型关联分析未显示较低的 P 值。 SNCA 是路易体的主要组成部分，因此 SNCA 的聚集被认为发挥着至关重要的作用。 SNCA 表达水平往往与尸检额皮质中相关等位基因的数量呈正相关，这些发现表明 SNCA 是散发性 PD 的明确易感基因。