Genetics of Parkonsonism

帕金森症的遗传学

• 批准号: 8540539
• 负责人: JEFFERY Marvin VANCE
• 金额: $ 7.65万
• 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/8540539
• 关键词: Affect; Age; Amish; Applied Genetics; Area; Bioinformatics; Biological; Biological Markers; Brain; Candidate Disease Gene; Cells; Cholecalciferol; Chromosomes; Chromosomes, Human, Pair 9; Clinical; Code; Coffee; Community Health Education; Complex; DNA Sequence; Data; Data Analyses; Data Set; Disease; Doctor of Philosophy; Early Diagnosis; Early treatment; Environmental Exposure; Epidemiologist; Etiology; Evaluation; Frequencies; Gene Cluster; Gene Expression Regulation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genomics; Goals; Growth; Human; Image; Individual; Institutes; Intervention; Mission; Mitochondria; Modeling; Molecular; Mutation; Nuclear; Parkinson Disease; Pathway interactions; Patients; Pesticides; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Population; Predisposition; Preventive; Principal Investigator; Proteins; Protocols documentation; RNA; RNA Sequences; Recording of previous events; Research; Research Infrastructure; Resources; Risk; Risk Factors; Role; Sampling; Series; Smoking; Symptoms; Techniques; Technology; Testing; Therapeutic; Training; Translating; Variant; Vision; Vitamin D; Work; Yeasts; Zebrafish; base; biological systems; clinical phenotype; cost; data management; disorder risk; environmental agent; epigenomics; exome; gene discovery; gene function; genetic linkage analysis; genetic pedigree; genome sequencing; genome wide association study; genome-wide; high risk; improved; induced pluripotent stem cell; innovation; insight; interest; multidisciplinary; nervous system disorder; next generation; prevent; programs; skills; success; therapeutic target; tool

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引起或有助于个人对帕金森氏病（PD）敏感的基因或遗传机制，并将这些发现转化为对风险或疾病的早期发现，并为PD提供治疗靶标。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，这些基因和途径可能对药物治疗或其他干预措施有用，以减缓疾病。项目1“通过整个外显子组测序（WES）在PD中识别稀有变体（RV）”将我们的工作从上一年开始，总计为1000名PD患者和1000个对照。通过基因组广泛的关联研究（GWAS）达到全基因组显着性的基因数量仍然很小且影响很小。这导致了这样的假设：遗传成分缺失。建议这种缺失的“遗传性”的最有可能的候选人是罕见的变体。途径分析和基因网络分析将包括更传统的频率分析。项目2“ PD中的长NCRNA作为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，细胞产生的很大一部分RNA来自不代表蛋白质（NCRNA）的DNA序列。最近的工作表明，NCRNA在神经系统疾病中对基因表达的调节中具有重要作用。该项目旨在确定有助于PD病因的关键NCRNA，并可以作为CSF疾病的生物标志物。项目3“维生素D浓度，遗传修饰剂和PD”是对维生素D（VID）的药物遗传学的研究。 研究表明，低VID是PD的危险因素。这项研究旨在在大型数据集中确认这一点，并定义基因VID相互作用，如果要成为预防性疗法，则必要。 该中心有4个核心：（a）具有教育和社区功能的行政功能（b）临床资源核心，（c）统计分析和生物信息学核心以及（d）一种新的，创新的核心，使用酵母，斑马鱼和诱导的多能干细胞的疾病iviodeling核心。 项目1 首席研究员：Jeffery M. Vance，医学博士，博士 标题：通过整个外显子组测序在PD中识别稀有变体 描述（由申请人提供）：帕金森氏病（PD）的遗传研究一直是促进研究巨大增长的主要工具。但是，越来越多的意识到，单独的常见变异（MAF> 5％）对患有PD和许多其他复杂疾病的风险的遗传贡献概不负责。 这种缺失的遗传贡献的替代假设之一是稀有变体。在过去的一年中，我们启动了帕金森氏病的第一个整个外显子组测序（WES）项目之一，以寻找有助于PD的稀有变体。该项目继续进行这项工作，将我们最近的途径工作纳入我们的分析中，并将提供有关发现基因的途径和功能的信息。 特定目标1在500名帕金森病患者的发现集中识别了一组稀有变体和其他SNP，在我们的复制数据集中进行了500个对照组，在特定的AIM 3A中进行了测试。 特定的目标2利用大型阿米什人的血统可以使用WES，靶向捕获和潜在的整个基因组测序来寻找稀有的变体。阿米什人提出了一群具有相对统一的环境暴露史和遗传同质性增加的个体。链接分析揭示了在血统的几个分支中染色体9的强大基因座，以及其他染色体上的其他基因座。因此，这是PD在杂种种群中的好模型。在特定目标3中，我们将在其他500例和500个对照中测试发现数据集的前200个基因和/或变体。 为了有效地完成此操作，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，包括通过变体，基因“群集”中的变体，途径分析，感兴趣的基因网络，例如线粒体核基因和AAO差异。为了改善途径的信息，还评估了鉴定的基因及其与其他已知PD基因的关系，我们将使用沉默和其他介入技术在三种不同的生物系统中通过核心D：酵母，斑马鱼和诱导的多能干细胞从PD患者和对照组中进行差异表达。