The hypothesis underlying the genome-wide association studies (GWAS) approach is that common variants underlie common diseases (CVCD). Most single nucleotide polymorphisms (SNPs) genotyped have minor allele frequencies at >5% frequency in the populations in which they were tested. Several GWAS have now been performed in PD. Primary results and subsequent meta-analyses show common genetic variability in alpha-synuclein (SNCA) and tau (MAPT) are major contributors to disease susceptibility, validating past discoveries. Other gene loci have been nominated and replicated, but with modest effects. Nevertheless, the precise gene and variant(s) driving most associations with disease have yet to be identified. For the most part, GWAS findings have not been directive for translational neuroscience.
Hence, the overall objective of this study is to test the hypothesis that multiple rare variants underlie common diseases (RVCD). Empirical genetic data strongly supports the RVCD hypothesis in Parkinson disease. One example is ancestral founder mutations in LRRK2 which have the highest population and allelic attributable risk. Many of the most pathogenic LRRK2 variants including R1441C/G/H, G2019S and G2385R were discovered and subsequently implicated in Parkinson disease by a combination of sequence analysis, with direct genotyping of the risk mutation across many populations and samples. In many instances we have found evidence for a common ancestral founder through subsequent microsatellite repeat (STR) genotyping providing additional support for pathogenicity. Other examples that rare variants may underlie common disease include findings in parkin, PINK1 and DJ-1 mutations in early-onset parkinsonism. Such gene/mutation mapping has recently been expedited through the application of next-generation sequencing (exome and whole genome), which led to discovery of VPS35 pD620N.
The vast majority of independent laboratories are not in a position to identify or investigate the frequency, penetrance or clinical phenotypes associated with rare variants, either because of a lack of power/appropriate samples or financial cost. The GEO-PD, because of its access to many samples of both familial and sporadic disease, and ethnically distinct patient samples and control groups, is uniquely positioned assess the frequency, disease prevalence and overall relevance of rare mutations for the global PD community.