The Genetic Core will assess the genetic contribution to familial Parkinson's disease and atypical parkinsonism. It will aid in molecular diagnosis for the Cinical and Neuropathology Cores and will serve Projects by Farrer and Dickson. Genes implicated in a phenotype of parkinsonism are to be sequenced and quantitatively assessed using Taqman/ABI3100 and fluorescent in-situ hybridization. Analysis will include all exons of the PRKN and DJ-1 genes in early-onset parkinsonism (<50 years at onset), as well as genes indirectly implicated either biochemically within a common pathway or through linkage/association analyses. The frequency of any variant found will be assessed in a large number of appropriate population controls. Genes/mutations will be cloned and made publically accessible to other researchers. Power analysis will prioritize family collections for the Clinical Core and guide pedigree expansion. Known loci will be examined through limited marker genotyping in regions implicated in previous genome searches, but for which the gene has yet to be identified (PARK3, 6, 8-11). The genetic contribution to disease in large multi-incident families, excluded from known loci, will subsequently be explored by genome-wide genotyping and model-based linkage and haplotype analyses. For smaller sets of families (2+ affecteds) or without a clearly demonstrable mode of inheritance, non-parametric allele sharing methods may be employed. Support will go into genetic analysis software, a package of perl scripts/open source statistical algorithms running on Linux OS, for wider distribution to other groups.
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