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

• 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
• 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

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.

我们过去在Udall中心申请的工作（2004-2009）提供了令人信服的遗传、基因组和生化证据，证明野生型a-突触核蛋白的过度表达是路易体病的主要危险因素。过去的基因发现立即改善了对罕见家族的诊断，并导致了业界赞助的针对a-突触核蛋白基因的RNA干扰的翻译项目。然而，我们的（PD， PDD， DLB和MSA）和a-synuclein的作用还处于起步阶段。项目1有四个目标来解决这些问题：目标1临床帕金森病多事件家族的外显子测序和尸检证实的路易体病。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经济有效的方法来识别新型