Single nucleotide and copy number variants associated with Parkinson disease

百万退伍军人计划(MVP)数据集将用于识别新的遗传风险变异- 包括拷贝数变异(CNV：基因组中的缺失和复制)-用于 帕金森病(PD)。以前确定的遗传风险因素将更好地描述为 测试所有成对的基因之间的相互作用，并测试是否存在与mRNA相关的变体 使用PrediXcan，表达水平可以预测帕金森病的风险。MVP摄入量调查问卷 捕获以前确定的环境风险因素，如头部创伤(创伤性脑 伤害)和农药暴露；这些将在研究中通过逐个基因- 环境测试，以确定变种的影响是否通过这些暴露而调节。这 也将是PD第一个分析重要的西班牙裔和非裔美国人的GWAS 这将揭示使用欧洲血统的个体识别的变异是否 可推广到其他人群。此外，较低者之间的关联的复制 可能会尝试血液和PD中的线粒体DNA拷贝数(MtDNA CN) 建立线粒体DNA CN作为帕金森病风险和进展的生物标记物，以后可以使用 在临床试验中，甚至在临床上。线粒体DNA CN将使用一种新的方法进行测量， 我们开发了用来确定GWAS上线粒体探针的相对信号强度的方法 与相应的核探测器信号强度进行比较。孟德尔式 然后，将采用随机实验来查看是否有证据表明低mtDNA CN是否导致PD或PD病理是否导致mtDNA CN减少。这些 实验将揭示有关帕金森病生物学的新信息，允许 更好的风险分层，并可能揭示新疗法的靶点。

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.