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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)是人类最常见的神经退行性疾病之一，以中脑黑质多巴胺能神经元丢失为特征。帕金森病是一种复杂的疾病，有多种遗传和环境因素影响疾病风险。为了确定散发性帕金森病的易感基因，我们对121个候选基因中的268个单核苷酸多态(SNPs)进行了病例对照关联研究。在两个独立的病例对照人群中，我们发现α-突触核蛋白(SNCA)中的一个SNP rs7684318与PD有最强的相关性(P=5.0x10^&lt；-10&gt；)。利用rs7684318附近的29个SNP进行的连锁不平衡分析表明，整个SNCA基因位于一个大小约120kb的单个连锁不平衡区块(D‘&gt；0.9)内。包括rs7684318在内的6个SNPs组成的紧密LD组(r^2&>0.85)，与PD关联最强(P=2.0x10^&9&gt；-1.7x10^&lt；-11&gt；)。单倍型关联分析未显示该组内任何单个SNP的P值低于任何单个SNP。SNCA是帕金森病的病理标志--路易体的主要成分。SNCA的聚集被认为在帕金森病中起着至关重要的作用。在尸检的额叶皮质中，SNCA的表达水平与相关等位基因的数量呈正相关。这些发现证实SNCA是散发性帕金森病的明确易感基因。