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识别导致或促成个体对帕金森病（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，并提供帕金森病的治疗靶点。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对患者的治疗，这些基因、遗传机制和途径可能有助于靶向药物治疗或其他干预措施以减缓疾病。项目 1“通过全外显子组测序 (WES) 鉴定 PD 罕见变异 (RV)”继续我们前一年的工作，总共有 1000 名 PD 患者和 1000 名对照者。通过全基因组关联研究（GWAS）达到全基因组显着性的基因数量仍然很少，而且影响也很小。这导致了一种假设，即存在缺失的遗传成分。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。路径分析和基因网络分析将包含在更传统的频率分析中。项目 2“长 ncRNA 作为 PD 中的表观基因组调节剂和 CSF 生物标志物”为 PD 带来了一个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RNA很大一部分来自不编码蛋白质的DNA序列（ncRNA）。最近的研究表明 ncRNA 在神经系统疾病的基因表达调控中发挥着重要作用。该项目旨在识别导致 PD 病因的关键 ncRNA，并可作为脑脊液疾病的生物标志物。项目 3“维生素 D 浓度、遗传修饰剂和 PD”是维生素 D (ViD) 药物遗传学的研究。 研究表明，低 ViD 是 PD 的危险因素。这项研究试图在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疗法，这将是必要的。 该中心有 4 个核心：(A) 具有教育和社区职能的行政管理 (B) 临床资源核心，(C) 统计分析和生物信息学核心，以及 (D) 一个新的创新核心，即使用酵母、斑马鱼和诱导多能干细胞的疾病 IVIodeling 核心。 项目1 首席研究员：Jeffery M. Vance，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) 的遗传学研究已成为推动研究巨大增长的主要工具。然而，人们越来越认识到，仅常见变异（MAF > 5%）并不能导致帕金森病和许多其他复杂疾病的遗传风险。 对于这种缺失的遗传贡献的替代假设之一是罕见变异。在过去的一年里，我们启动了第一个针对帕金森病的全外显子组测序 (WES) 项目，以寻找导致帕金森病的罕见变异。该项目继续这项工作，将我们最近在通路方面的工作纳入我们的分析中，并将提供有关所发现基因的通路和功能的信息。 具体目标 1 在 500 名帕金森病患者和 500 名对照的发现组中确定了一组初始罕见变异和其他 SNP，以便在具体目标 3a 中的复制数据集中进行测试。 Specific Aim 2 利用大量阿米什血统，利用 WES、靶向捕获和潜在的全基因组测序来寻找罕见变异。阿米什人呈现出一组具有相对一致的环境暴露史和更高的遗传同质性的个体。连锁分析揭示了该谱系的几个分支中 9 号染色体上的强基因座，以及其他染色体上的其他基因座。因此，这是近交群体中 PD 的良好模型。在特定目标 3 中，我们将在另外 500 个病例和 500 个对照中测试发现数据集中的前 200 个基因和/或变异。 为了有效地实现这一目标，我们将为下一代测序创建目标捕获。 该验证数据集的分析将包括数据的多个子集，包括变体、基因“簇”内的变体、通路分析、感兴趣的基因网络（例如线粒体核基因和 AAO 差异）。为了完善有关通路的信息并评估已识别的基因及其与其他已知 PD 基因的关系，我们将通过 Core D 使用沉默和其他介入技术检查候选基因在三个不同生物系统中的差异表达：酵母、斑马鱼和源自 PD 患者和对照的诱导多能干细胞。