Identification of a genes for Parkinson's disease

帕金森病（PD）是一种复杂的疾病，多种遗传和环境因素影响其发病风险。虽然最近已经确定了孟德尔遗传性帕金森病的几个致病基因，但尚未确定影响特发性帕金森病的强遗传因素。为了确定特发性帕金森病的易感基因，我们在基因组中以100kb的间隔排列了27000个微卫星标记，进行了一项全基因组关联研究。为了进行初步筛选，我们比较了124名PD患者和124名对照组的聚合DNA PCR产物的模式。我们分析了27000个标记，发现7.8%的标记有相关性（p<0.05）。然后，我们对所有这些候选标记进行了系统和全面的第二次和第三次筛选，使用其他集合DNA来排除假阳性关联。预计在三次筛查中，大约有30个标记会显示出显著的关联。其次，我们利用多个候选基因的snp进行了病例对照分析。我们从家族性PD、多巴胺能神经元、营养因子、氧化应激、线粒体、细胞凋亡、泛素-蛋白酶体、自噬等方面筛选候选基因。为了进行初步筛选，我们用Invader方法对190名患者和190名对照组进行了基因分型。在122个候选基因的267个snp中，16个基因的22个snp差异有p<0.05。我们现在通过将患者和对照组的样本数量分别增加到近900个和900个来确认这些关联。与这些标记的连锁不平衡中的snp可能与PD的发病机制有关。

Parkinson's disease (PD) is a complex disorder with multiple genetic and environmental factors influencing disease risk. Although several causal genes for Mendelian inherited PD have recently been identified, strong genetic factors that influence idiopathic PD have not yet been identified. To identify susceptibility genes for idiopathic PD, we performed a genome-wide association study using 27,000 microsatellite markers arranged at intervals of 100kb throughout the genome. For the initial screening, we compared the pattern of the PCR products of pooled DNA from 124 patients with PD and 124 controls. We analyzed the 27,000 markers and found associations (p<0.05) in 7.8% of the markers. Then, we have performed systematic and comprehensive 2nd and 3rd screenings on all of these candidate markers using other sets of pooled DNA to exclude false positive associations. and expect that approximately 30 markers will show significant associations throughout all three screenings.Secondly, we have done case-control analysis by using SNPs in multiple candidate genes. We selected candidate genes from the viewpoints of familial PD, dopaminergic neurons, trophic factors, oxidative stress, mitochondria, apoptosis, ubiquitin-proteasome, autophagy, etc. For initial screening, we genotyped 190 patients and 190 controls by Invader method. Of 267 SNPs in 122 candidate genes, 22 SNPs in 16 genes showed p<0.05. We are now confirming these associations by increasing the number of samples to nearly 900 for patients and 900 for controls.SNPs in linkage disequilibrium with these markers may be associated with the pathogenesis of PD.