Parkinson's disease (PD) is a neurodegenerative disorder affecting over 1,000,000 people in the United States. Onset symptoms are variable and generally occur late in life. The mode of inheritance for the vast majority of familial PD cases is unknown. A number of candidate genes have been suggesting including CYP2D, APOE, and interleukin 2 using case/control studies but these loci have not been consistently replicated, emphasizing the problem with case/control design. A very small percentage of PD cases have autosomal dominant inheritance. Recently mutations in the alpha-synuclein gene have been identified as the cause of a very rare form of autosomal dominant early-onset PD but the genes underlying the common late-onset PD remain unknown. The investigators have ascertained and sampled 215 independent discordant sibships with familial PD and are continuing to collect an additional 200 familial PD-discordant sibships for testing of positive results from the first dataset. In addition, they will collect 400 sets of discordant sibpairs with sporadic PD. These families will form the basis for association testing using sib disequilibrium methods, which will circumvent some of the problems with the case/control approach. The investigators will test for association candidate genes identified in the literature, in their own linkage screens, and through the SAGE analysis in Project II of this proposal in order to identify genes underlying the complex etiology of PD. Risk factor information will be available for gene/ environmental investigations through Project III of this proposal once susceptibility genes are identified. In addition, methods will be developed to adjust for uncertainty in status of unaffected siblings in the discordant sibship tests, and to adjust for multiple tests at tightly linked markers. These studies will help define the underlying etiology of this complex disease.
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