Identification of genetic risk factors that predict disease onset, susceptibility

识别预测疾病发作和易感性的遗传风险因素

基本信息

批准号：
8011766
负责人：
MATTHEW J FARRER
金额：
$ 48.48万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011766
关键词：
Affect Autopsy Basal Ganglia Biochemical Brain Clinical Clinical Data Code Complement Computer Simulation Data Data Analyses Databases Diagnosis Disease Etiology Exhibits Family Family member Freezing Frequencies Future Gene Expression Profile Gene Mutation Genes Genetic Genetic Polymorphism Genome Genomics Genotype Haplotypes Homologous Gene Industry Joints Lead Lewy Bodies Lewy Body Disease Libraries Linkage Disequilibrium Logistic Regressions Luciferases Messenger RNA Methods MicroRNAs Molecular Molecular Diagnosis Molecular Profiling Mutation Onset of illness Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phenotype Pilot Projects Predisposition Protein Isoforms Proteins RNA Interference RNA Splicing Reading Regulation Reporter Research Resources Rest Risk Risk Factors Role Running SNP genotyping Sampling Series Tissues Transcript Untranslated Regions Variant Work alpha synuclein base brain tissue comparative cost effective disorder risk dosage gene discovery genetic analysis genetic association genetic pedigree genetic risk factor genome wide association study genome-wide genome-wide linkage improved infancy inhibitor/antagonist kindred next generation novel proband programs prospective segregation

Affect Autopsy Basal Ganglia Biochemical Brain Clinical Clinical Data Code Complement Computer Simulation Data Data Analyses Databases Diagnosis Disease Etiology Exhibits Family Family member Freezing Frequencies Future Gene Expression Profile Gene Mutation Genes Genetic Genetic Polymorphism Genome Genomics Genotype Haplotypes Homologous Gene Industry Joints Lead Lewy Bodies Lewy Body Disease Libraries Linkage Disequilibrium Logistic Regressions Luciferases Messenger RNA Methods MicroRNAs Molecular Molecular Diagnosis Molecular Profiling Mutation Onset of illness Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phenotype Pilot Projects Predisposition Protein Isoforms Proteins RNA Interference RNA Splicing Reading Regulation Reporter Research Resources Rest Risk Risk Factors Role Running SNP genotyping Sampling Series Tissues Transcript Untranslated Regions Variant Work alpha synuclein base brain tissue comparative cost effective disorder risk dosage gene discovery genetic analysis genetic association genetic pedigree genetic risk factor genome wide association study genome-wide genome-wide linkage improved infancy inhibitor/antagonist kindred next generation novel proband programs prospective segregation

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项目摘要

Work from our past Udall Center application (2004-2009) provides compelling genetic, genomic and biochemical evidence that over-expression of wild-type a-synuclein is a major risk factor for Lewy body disease. Past genetic discovery has immediately improved diagnoses for rare families, and has lead to industry-sponsored translational programs in RNA interference targeting the a-synuclein gene. However, our (PD, PDD, DLB and MSA), and the role of a-synuclein is in its infancy. Project 1 has four aims to addr s these issues: Aim 1 Exonic sequencing of multi-incident family with clinical parkinsonism and autopsy confirmed Lewy body disease. As our preliminary data illustrates, the methods used provide a rapid and cost effective way to identify novel gene mutation(s) in disease. Aim 2 is for comprehensive SNCA genomic capture and re-sequencing of asynucleinopathies, to enable comparative genetic association studies of clinical and pathologic phenotypes across a range of Lewy body disorders. We need to identify the precise variants that influence disease risk, and their molecular mechanism. Work in Aim 3, using a subset of the best characterized samples, will provide complementary data from whole genome transcriptome analysis in a-synucleinopathies. Lastiy, Aim 4 will characterize the role of endogenous miRNA in the regulation of a-synuclein expression. The project could not be accomplished outside of a Center; it rests heavily on resources and expertise offered by Cores B, C and D, and will reciprocally inform research in Projects 2 & 3. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases. We aim to provide a mechanistic understanding of the pathogenesis of Lewy body disorders through gene discovery, and for a-synuclein and its homologues, exploiting advances in next-generation sequencing methods.

我们过去的Udall Center应用程序（2004-2009）的工作提供了引人入胜的遗传，基因组和生化证据，即野生型A-突触核蛋白的过表达是Lewy身体疾病的主要危险因素。过去的遗传发现立即改善了稀有家庭的诊断，并导致了针对A-核蛋白基因的RNA干扰的行业赞助的转化程序。但是，我们的（PD，PDD，DLB和MSA）以及A-核蛋白的作用仍处于起步阶段。项目1具有四个旨在增加以下问题的目的：目标1具有临床帕金森氏症和尸检的多物种家族的外显子测序证实了刘易体内疾病。正如我们的初步数据所示，所使用的方法提供了一种快速且具有成本效益的方法来识别新颖的方法疾病中的基因突变。 AIM 2是为了全面的SNCA基因组捕获和对异核病态病的重新测试，以实现对一系列路易斯体疾病的临床和病理表型的比较遗传关联研究。我们需要确定影响疾病风险及其分子机制的精确变体。在AIM 3中使用最佳特征样本的子集的工作将提供来自A-突触核酸的整个基因组转录组分析的互补数据。 Lastiy，AIM 4将表征内源miRNA在调节A核蛋白表达中的作用。该项目无法在中心之外完成；它在很大程度上取决于核心B，C和D提供的资源和专业知识，并将在项目2＆3中的研究中相互告知。我们的目标是提供有意义的分子诊断以重新分类这种异质性疾病。我们旨在通过基因发现以及A-突触核蛋白及其同源物提供对Lewy身体疾病的发病机理的机械理解，从而利用了下一代测序方法的进步。