? ? The long-term objectives of the proposed studies are to clarify the etiology of Parkinson's Disease (PD) and to identify means to prevent it. Specifically, the investigators will conduct a series of genetic association studies in 800 PD, 1,222 siblings, and 800 unrelated controls (2,822 subjects total).
The first aim will be to study the impact of population admixture and study design on genetic associations, through the independent comparison of the same PD cases with unaffected siblings and unrelated controls.
The second aim will be to identify susceptibility genes for PD through association based genome wide (""""""""top down"""""""") and candidate gene (""""""""bottom up"""""""") studies. Specifically, the investigators will conduct a genome wide scan for association in their subjects using at least 1,494 single nucleotide polymorphism markers. They will seek to replicate associations through a similar genome wide scan in an independent sample of cases and controls (provided through collaboration). The investigators will also study the association of at least 24 candidate genes with PD. This will include genes related to the ubiquitin proteasomal pathway and genes related to cellular compartmentalization of neurotoxins and possibly neuroprotection. They will consider allele and haplotype variants. The investigators will compare cases independently to unaffected siblings and to unrelated controls.
The third aim will explore possible gene-gene and gene-environment interactions in PD through recursive partitioning and conditional logistic regression models. The investigators have previously observed gene by gene by gender interactions in PD, and will build more complex models to include multiple genotypes and environmental exposures. This application is submitted as a competing supplement application to the """"""""Molecular Epidemiology of Parkinson's Disease"""""""" (ES10751) grant and bridges these activities with those of the second grant """"""""Epidemiology and Genetics of Parkinson's Disease"""""""" (NS33978). The proposed aims represent a significant amplification and expansion of the investigators' ongoing work. The proposed studies will provide an invaluable genetic framework for anticipated toxicogenomic studies of PD. ? ? ?
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