Genome wide SNP analysis in Parkinson's disease

许多神经系统疾病的遗传因素被认为本质上是复杂的，疾病风险是由人类基因组中常见的风险等位基因组合驱动的。最近，国际单倍型图谱项目I和II阶段的完成以及高plex SNP检测的可用性使得全基因组范围内常见遗传变异性的检测成为一项现实的努力。我们使用来自NIH资助的神经遗传学库的500000个snp对帕金森病队列进行了全基因组关联分析。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。这项工作已经导致SNCA和MAPT的共同变异性被确定为帕金森病的明确危险因素。

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)