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 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. In addition a fifth stage analysis, currently under review, has revealed a large number of additional loci.
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