Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease
Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson's disease
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DOI：
10.1093/hmg/ddl030
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发表时间：
2006-04-01
影响因子：
3.5
通讯作者：
Toda, T
中科院分区：
文献类型：
--
作者：
Mizuta, I;Satake, W;Toda, T
帕金森病（Parkinson's disease，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的缺失为特征。PD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PD的易感基因，我们对121个候选基因中的268个单核苷酸多态性（SNP）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SNP rs7684318与PD的相关性最强（P=5.0x10（-10））。使用rs7684318周围区域中的29个SNP进行的连锁不平衡（LD）分析揭示，整个SNCA基因位于跨越类似于120 kb的单个LD区块（D '> 0.9）内。包括rs7684318在内的6个SNP的紧密LD组（r（2）> 0.85）与PD最强相关（P=2.0x10（-9）-1.7x10（-11））。单倍型关联分析没有显示出比该组内任何单个SNP更低的P值。SNCA是路易体的主要成分，路易体是PD的病理标志。SNCA的聚集被认为在PD中起关键作用。SNCA表达水平往往与尸检额叶皮质中相关等位基因的数量呈正相关。这些发现确立SNCA作为散发性PD的明确易感基因。
Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the 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 alpha-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 similar to 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 with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.