Genetics of Parkonsonism

帕金森症的遗传学

• 批准号: 8263842
• 负责人: JEFFERY Marvin VANCE
• 金额: $ 186.84万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263842
• 关键词: Genetics; Parkonsonism

DESCRIPTION (provided by applicant): The overall goal of the center is to identify genes or genetic mechanisms that cause or contribute to an individual's susceptibility to Parkinson Disease (PD) and to translate these discoveries into early detection of risk or disease, as well as provide therapeutic targets for PD. Our long-term goals include improving therapy for patients by providing important genes, genetic mechanisms and pathways that may be useful to target with drug treatment or other intervention to slow the disease. Project 1 "Identification of rare variants (RV) in PD through whole exome sequencing (WES)" continues our work from the previous year in at total of 1000 PD patients and 1000 controls. The number of genes which have reached genome-wide significance through genome wide association studies (GWAS) remains small and with small effect. This has led to the hypothesis that there is a missing genetic component. The most likely candidate for this missing "hereditability" has been suggested to be rare variants. Pathway analyses and gene network analyses will be included with more traditional frequency analyses. Project 2 " Long ncRNAs as epigenomic modulators and CSF biomarkers in PD" brings an exciting new area of research to PD. Recent RNA sequencing studies have shown that a large proportion of RNA produced by the cell comes from DNA sequence that does not code for protein (ncRNA). Recent work has shown an important role in the regulation of gene expression by ncRNAs in neurological disease. This project seeks to identify key ncRNAs that contribute to the etiology of PD and could serve as biomarkers of disease in CSF. Project 3 "Vitamin D concentration, genetic modifiers, and PD" is a study of the pharmacogenetics of Vitamin D (ViD). Studies have suggested that low ViD is a risk factor for PD. This study seeks to confirm this in a large dataset, and define the gene-ViD interactions that will be necessary if it is to become preventive therapy. The Center has 4 cores: (A) Administrative with Education and Community functions (B) Clinical Resource Core, (C) Statistical Analysis and Bioinformatics Core and (D) a new and innovative core, the Disease IVIodeling Core using yeast, zebrafish and induced pluripotent stem cells. PROJECT 1 Principal Investigator: Jeffery M. Vance, MD, PhD Title: Identification of Rare Variants in PD through Whole Exome Sequencing Description (provided by applicant): Genetic studies in Parkinson Disease (PD) have been a major tool fueling the tremendous growth in research. However, there is increasing realization that common variations (MAF > 5%) alone are not responsible for the genetic contribution to risk for developing PD and many other complex disorders. One of the alternative hypothesis for this missing genetic contribution are rare variants. Over the past year we initiated one of the first whole exome sequencing (WES) projects for Parkinson disease to search for rare variants contributing to PD. This project continues this work, incorporates our recent work on pathways into our analyses, and will provide information on the pathways and function of the genes discovered. Specific Aim 1 identifies an initial set of rare variants and additional SNPs in a discovery set of 500 Parkinson Disease patients and 500 controls for testing in our replication dataset in Specific Aim 3a. Specific Aim 2 utilizes a large Amish pedigree to look for rare variants using WES, targeted capture and potentially whole genome sequencing. The Amish present a group of individuals with both a relatively uniform environmental exposure history and increased genetic homogeneity. Linkage analysis reveals a strong locus on chromosome 9 In several branches of the pedigree, and additional loci on other chromosomes. This is thus a good model for PD in the outbred population. In Specific Aim 3 we will test the top 200 genes and/or variants from our discovery dataset in an additional 500 cases and 500 controls. To accomplish this efficiently we will create a targeted capture for next generation sequencing. Analyses of this verification datasets will include multiple subsets of the data including by variant, variants within a gene "cluster", pathway analyses, gene networks of interest such as mitochondrial nuclear genes and AAO differences. In order to improve information on pathways and also evaluate the identified genes and their relationship to other known PD genes, we will examine differentially expression using silencing and other interventional techniques for the candidate genes in three different biological systems through Core D: yeast, zebrafish and induced pluripotent stem cells derived from PD patients and controls.

描述（由申请人提供）：该中心的总体目标是确定导致或有助于个体对帕金森病（PD）易感性的基因或遗传机制，并将这些发现转化为风险或疾病的早期检测，以及为PD提供治疗靶点。我们的长期目标包括通过提供重要的基因、遗传机制和途径来改善患者的治疗，这些基因、遗传机制和途径可能有助于药物治疗或其他干预措施来减缓疾病。项目1“通过全外显子组测序（WES）鉴定PD中的罕见变异（RV）”继续了我们去年在总共1000名PD患者和1000名对照中的工作。通过全基因组关联研究（GWAS）达到全基因组意义的基因数量仍然很少，影响也很小。这导致了一个假设，即有一个缺失的遗传成分。这种缺失的“遗传性”最有可能的候选者被认为是罕见的变异。通路分析和基因网络分析将与更传统的频率分析一起纳入。项目2“长ncRNA作为PD的表观基因组调节剂和CSF生物标志物”为PD带来了令人兴奋的新研究领域。最近的RNA测序研究表明，细胞产生的大部分RNA来自不编码蛋白质的DNA序列（ncRNA）。最近的研究表明，ncRNA在神经系统疾病中的基因表达调控中起着重要作用。该项目旨在确定有助于PD病因学的关键ncRNA，并可作为CSF中疾病的生物标志物。项目3“维生素D浓度，遗传修饰剂和PD”是维生素D（ViD）的药物遗传学研究。 研究表明，低ViD是PD的风险因素。这项研究试图在一个大型数据集中证实这一点，并定义基因-ViD相互作用，如果它要成为预防性治疗，这将是必要的。 该中心有四个核心：（A）具有教育和社区功能的行政管理（B）临床资源核心，（C）统计分析和生物信息学核心，以及（D）新的和创新的核心，使用酵母、斑马鱼和诱导多能干细胞的疾病IVIodeling核心。 项目1 主要研究者：Jeffery M.万斯，医学博士，哲学博士 标题：通过全外显子组测序鉴定PD罕见变异 描述（由申请人提供）：帕金森病（PD）的遗传学研究一直是推动研究巨大增长的主要工具。然而，越来越多的人认识到，常见的变异（MAF > 5%）本身并不是导致PD和许多其他复杂疾病风险的遗传因素。 这种缺失的遗传贡献的替代假设之一是罕见的变异。在过去的一年里，我们启动了帕金森病的第一个全外显子组测序（WES）项目，以寻找导致PD的罕见变异。该项目继续这项工作，将我们最近对通路的研究纳入我们的分析，并将提供有关所发现基因的通路和功能的信息。 Specific Aim 1在500名帕金森病患者和500名对照的发现集中鉴定了一组初始的罕见变异和额外的SNP，用于在Specific Aim 3a的复制数据集中进行测试。 Specific Aim 2利用一个庞大的Amish谱系，使用WES、靶向捕获和潜在的全基因组测序来寻找罕见的变异。阿米什人是一群既有相对统一的环境暴露史，又有较高的遗传同质性的个体。连锁分析显示，在9号染色体上的一个强位点在几个分支的系谱，和其他染色体上的附加位点。因此，这是远系繁殖群体中PD的良好模型。在Specific Aim 3中，我们将在另外500例病例和500例对照中测试我们发现数据集中的前200个基因和/或变体。 为了有效地实现这一点，我们将为下一代测序创建靶向捕获。 该验证数据集的分析将包括多个数据子集，包括变异、基因“簇”内的变异、途径分析、感兴趣的基因网络（如线粒体核基因和AAO差异）。为了改善途径的信息，并评估已鉴定的基因及其与其他已知PD基因的关系，我们将通过Core D研究三种不同生物系统中候选基因的沉默和其他干预技术的差异表达：酵母，斑马鱼和来自PD患者和对照的诱导多能干细胞。