Genome wide SNP analysis in Parkinson's disease

许多神经系统疾病的遗传因素被认为是复杂的，疾病风险是由人类基因组中常见的风险等位基因的组合驱动的。最近，国际单倍型图计划第一和第二阶段的完成以及高复杂SNP检测的可用性使得全基因组常见遗传变异性的检测成为现实的奋进。我们应用了全基因组关联分析，使用500，000个SNP对NIH资助的神经遗传学库中的帕金森病队列进行了分析。我们与来自德国、美国、英国和日本的合作者结合了这项工作的数据。这项工作导致SNCA和MAPT的常见变异性被鉴定为帕金森病的明确风险因素。 我们现在已经扩展了这项工作，并将结果与PD和相关疾病的其他大型基因分型项目相结合，以确定这种疾病的其他风险位点，确定帕金森病的其他15个风险位点。这项工作首次明确证明帕金森病的遗传基础是复杂和实质性的。这一努力不仅揭示了一个比以前认为的更大的遗传成分，而且还提名了一系列新的靶点，以了解帕金森病的生物学基础。 我们最近对PD GWA的大荟萃分析是所有在白人PD受试者中生成GWA数据的组之间的大型协作努力。该分析揭示了大约30个基因座，并且我们已经在一个独立的系列中完成了这些基因座的复制。 这项工作的下一个组成部分涉及大规模重新测序，以找到介导常见风险的生物学相关变异，此外还负责罕见的因果突变。 我们最近完成了该分析的第二阶段，该阶段基于扩展当前的横断面队列，并在PD患者的纵向队列中完成了正在进行的全基因组关联研究，以确定进展、治疗反应和合并症的风险位点。这已经确定了大约80个PD的遗传风险因素（30个在印刷中，50个在准备中）

The genetic contribution to a number of neurological disorders is thought to be complex in nature, disease risk being driven by a combination of risk alleles commonly present in the human genome. Recently the completion of stages I and II of the international Haplotype Map project and the availability of high-plex SNP assays has made genome wide assay of common genetic variability a realistic endeavor. We have applied genome wide association analysis using 500,000SNPs to a Parkinsons disease cohort from the NIH funded neurogenetics repository. We have combined the data from this work with collaborators from Germany, the US, the UK and Japan. This work has lead to the identification of common variability in SNCA and MAPT as unequivocal risk factors for Parkinson's disease. We have now extended this work and combined results with other large genotyping projects in PD and related diseases to identify additional risk loci for this disease, identifying an additional 15 risk loci for Parkinson's disease. This work showed for the first time unequivocal evidence that the genetic basis of Parkinson's disease is complex and substantive. Not only has this effort revealed a greater than previously thought genetic component, but it has also nominated a host of new targets with which to understand the biological basis of Parkinson's disease. Our most recent mega-meta analysis of PD GWA is a large collaborative effort between all groups that have generated GWA data in Caucasian PD subjects. This analysis has revealed approximately 30 loci, and we have completed replication of these in an independent series. The next component of this work involves large scale resequencing to find biologically relevant variants that mediate the common risk and in addition are responsible as rare causal mutations. We have recently completed a second stage of this analysis based on expanding the current cross sectional cohort and also completing an ongoing genome wide association study in a longitudinal cohort of PD patients to identify risk loci for progression, response to treatment, and comorbidities. This has identified approximately 80 genetic risk factors for PD (30 in press, 50 in preparation)