Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting nearly 500,000 Americans. Although five genes have been identified which can directly cause PD when mutated, these genes likely contribute to disease in far fewer than 5% of all PD patients. Six Genome-Wide Association Studies (GWAS) have been or are in the process of being completed to identify common variants contributing to PD susceptibility and/or age of disease onset. There has been very limited overlap among the top SNPs or genes nominated in the four studies that have been publicly reported. At least two studies have reported support for an association with SNCA and MAPT. However, no cohesive analysis, like that proposed here, has been performed on these large GWAS studies. Based on the relative risk of PD to first degree relatives, and the numerous candidate genes that have been confirmed by multiple laboratories to have association with PD risk and age-of-onset (i.e. GBA, MAPT), it would appear highly likely that additional genes, not yet identified, must also contribute to PD susceptibility. In this application, we propose to create the PD GWAS Consortium which will collaboratively use the clinical and biological resources of the PD genetics research community to identify genes contributing to PD. The PD GWAS Consortium will consist not only of investigators from most of the groups generating PD GWAS data, but will also include investigators providing independent replication samples. This collaborative group will pursue four specific aims: 1) Perform meta and pooled analyses across the GWAS data available from six independent studies to identify the SNPs providing the strongest evidence of association with PD susceptibility (5,113 cases;5,327 controls) and age of onset (5,113 PD cases) across studies. 2) Perform pooled analysis across the GWAS data available from five independent studies (4,670 cases;4,884 controls) to identify copy number variants providing the strongest evidence of association with PD susceptibility and age of onset across studies. 3) Perform analyses in the five independent GWAS studies containing smoking data to test for gene x smoking interactions that may contribute to PD susceptibility or age of onset. 4) Genotype 384 SNPs in the genes of highest priority in a replication sample of 2,976 PD cases and 2,976 controls never included in a previous GWAS. The studies proposed herein will allow us to rapidly advance PD genetics, poise the field to pursue further studies of the most promising genomic variation and lead to a better understanding of the mechanisms contributing to disease risk and age of onset.
We propose to create the PD GWAS Consortium which will collaboratively use the clinical and biological resources of the PD genetics research community to identify genes contributing to PD. We will jointly perform analyses of datasets from six genomewide association studies consisting of over 5,000 PD cases and 5,000 controls and identify SNPs and genes contributing to the risk of PD and the age of PD onset. We will also perform analyses to test whether the effect of some genes is moderated by smoking. Finally, we will replicate our most promising SNPs and genes in a sample of nearly 3,000 PD cases and 3,000 controls.
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