Single nucleotide and copy number variants associated with Parkinson disease

与帕金森病相关的单核苷酸和拷贝数变异

• 批准号: 10409630
• 负责人: JAMES ASHE
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409630
• 关键词: Address; Affect; African American; Area; Biological; Biological Markers; Biology; Blood Tests; Cholesterol; Clinic; Clinical; Clinical Trials; Collection; Communities; Computer software; Copy Number Polymorphism; Craniocerebral Trauma; DNA; DNA copy number; Data; Data Set; Disease; Disease Progression; Environment; Environmental Risk Factor; European; Exposure to; Future; Gene Expression; General Population; Genes; Genetic; Genetic Risk; Genome; Genotype; Goals; Hematological Disease; Heritability; Hispanic Americans; Hispanics; Individual; Intake; Intervention Trial; Java; Learning; Lipids; Measures; Mediating; Mendelian randomization; Meta-Analysis; Mitochondria; Mitochondrial DNA; Molecular; Morbidity - disease rate; Mutation; Natural Selections; Neurodegenerative Disorders; Noise; Nuclear; Nucleic Acid Regulatory Sequences; Nucleotides; Parkinson Disease; Participant; Pathology; Patient Care; Patients; Pesticides; Pharmaceutical Preparations; Population; Population Study; Quantitative Trait Loci; Questionnaires; Research Personnel; Resources; Rest; Risk; Running; Sample Size; Secondary to; Series; Signal Transduction; Single Nucleotide Polymorphism; Susceptibility Gene; Test Result; Testing; Transcript; Traumatic Brain Injury; United States Department of Veterans Affairs; Variant; Veterans; base; clinical care; disorder risk; drug development; experimental study; gene environment interaction; gene interaction; genetic linkage analysis; genetic risk factor; genetic testing; genetic variant; genome wide association study; genome-wide; improved; instrument; interest; mRNA Expression; mitochondrial dysfunction; mortality; new therapeutic target; novel; novel strategies; pesticide exposure; programs; randomized trial; response; risk stratification; risk variant; therapeutic target; trait

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.

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（CNVs：基因组中的缺失和重复）-对于 帕金森病（PD）。以前确定的遗传风险因素将更好地表征， 测试所有成对的基因与基因的相互作用， 表达水平是使用PrediXcan预测PD风险的指标。MVP入选问卷 捕获先前确定的环境风险因素，例如头部创伤（创伤性脑损伤 伤害）和农药暴露;这些将通过基因- 环境测试，以确定这些暴露是否介导了变异的影响。这 这也将是PD的第一个GWAS，以分析重要的西班牙裔和非洲裔美国人， 人群，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，复制的关联之间的较低 将尝试检测血液中的线粒体DNA拷贝数（mtDNA CN）， 建立mtDNA CN作为PD风险和进展的生物标志物，以后可以使用 在临床试验中，甚至在临床上。mtDNA CN将使用一种新的方法进行测量， 我们开发了GWAS上线粒体探针的相对信号强度， 阵列与核探针的相应信号强度进行比较。孟德尔 随机化实验，然后将采用，看看是否有证据表明，低mtDNA CN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， 更好的风险分层，并可能揭示新疗法的靶点。