The Million Veteran Program (MVP) data set will be used to identify new genetic risk variants? including copy number variants (CNVs: deletions and duplications in the genome)?for Parkinson disease (PD). Previously identified genetic risk factors will be better characterized by testing all pairwise gene-by-gene interactions and testing if variants associated with mRNA expression levels are predictive of PD risk using PrediXcan. The MVP intake questionnaire captured previously identified environmental risk factors such as head trauma (traumatic brain injury) and pesticide exposure; these will be accounted for in the study through gene-by- environment tests to determine if the effects of variants are mediated by these exposures. This will also be the first GWAS of PD to analyse significant Hispanic and African American populations, which will reveal if the variants identified using individuals of European descent are generalizable to other populations. In addition, replication of an association between lower mitochondrial DNA copy number (mtDNA CN) in the blood and PD will be attempted, possibly establishing mtDNA CN as a biomarker for PD risk and progression, which could later be used in clinical trials or even in the clinic. mtDNA CN will be measured using a novel approach that we developed to determine the relative signal intensity for mitochondrial probes on a GWAS array compared to the corresponding signal intensity for nuclear probes. Mendelian randomization experiments would then be employed to see if there is evidence that low mtDNA CN causes PD or whether the PD pathology causes the mtDNA CN to decrease. These experiments will reveal new information regarding the biology of Parkinson disease, allow for better risk stratification, and potentially reveal targets for novel therapeutics.
The first goal of this project is to identify novel changes in DNA that increase the risk of Parkinson disease (PD). These could include a variety of mutations, where a gene or part of a gene is deleted or duplicated. By comparing the genetic data of otherwise healthy individuals to those who have had a traumatic brain injury or were routinely exposed to pesticides, this study hopes to identify the specific mutations affecting PD risk when combined with these external factors. This information would aid in the identification and prioritization of potential biological targets for future drug development. The second goal of this project is to determine if a blood test that measures mitochondrial DNA can predict PD risk or the progression of PD. This could aid in clinical trials or, as therapies improve, could function as a clinical early warning to guide treatment, in the same way that doctors today will prescribe lipid-lowering medication in response to high cholesterol test results.
