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Analysis and characterization of a cohort of familial Parkinson's disease exomes

家族性帕金森病外显子组的分析和表征

基本信息

批准号：
9268096
负责人：
TATIANA M. FOROUD
金额：
$ 67.96万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9268096
关键词：
Adult Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Award Biological Assay Biological Models Bradykinesia Candidate Disease Gene Collaborations Communities Data Defect Development Disease Drosophila genus Etiology Family Family member Gene Frequency Generations Genes Genetic Inherited Institutes International Knowledge LRRK2 gene Late-Onset Disorder Mendelian disorder Methodology Muscle Rigidity Mutation National Heart, Lung, and Blood Institute Nature Neurodegenerative Disorders PINK1 gene Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Patients Population Prevalence Proteins RNA Splicing Research Research Personnel Rest Tremor Sampling Series Source Structure Substantia nigra structure Testing United States National Institutes of Health Validation Variant Yeast Model System alpha synuclein base case control cohort early onset exome exome sequencing genetic pedigree genetic variant genome-wide indexing induced pluripotent stem cell new therapeutic target novel parkin gene/protein posture instability public health relevance rare variant

项目摘要

DESCRIPTION (provided by applicant) Parkinson's disease (PD) is an adult-onset neurodegenerative disease of the substantia nigra characterized by resting tremor, bradykinesia, muscular rigidity and postural instability and represents the second most common cause of neurodegenerative disease. Unfortunately, it is estimated that only ~30-40% of the underlying genetic causes of familial form of PD have been explained to date. The identification of causative mutations for Mendelian disorders is critical fo our understanding of their pathogenesis. As part of a NIH High Priority, Short-Term Project Award (R56NS082349), we are currently performing at the Center for Inherited Disease Research (CIDR) exome sequencing of 1,567 familial PD cases. These PD patients are from 1,089 familial PD pedigrees, including multiple PD cases from 440 pedigrees. We propose a series of aims that will leverage the information gained from these exomes to identify novel genes contributing to PD and then explore the functional effect of the genes/variants identified through functional studies. The Specific Aims of this proposal are: (1.) Discovery of Novel Genes Associated with Familial PD. We will employ two complementary approaches to identify novel genes associated with familial PD. (Approach #1) Identified variants will be filtered based on several criteria to generate a narrowed set of candidate variants. Candidate variants/genes observed in multiple families will be given highest priority. (Approach #2) The exomes of index PD cases will be subject to an unbiased genome-wide rare variant analysis by comparing to the raw data of over 20,000 control samples derived from several sources. The top 25 candidate genes from each approach will be validated and characterized in Aim #2. (2) Validation/Characterization of Novel Genes Associated with Familial PD. Top candidate genes from Aim #1 will be validated in an independent replication cohort of over 800 familial PD and ~5,000 control exomes. Variants that do not segregate properly or are present at a signification percentage in controls will be excluded and the candidate gene re-evaluated. The broader importance of our candidate genes will be tested in a cohort of over 3,000 sporadic PD exomes. Genes will be prioritized based on several criteria including the functional impact of the variants identified, variant allele frequencies and eQTL and splicing analysis. (3) Functional Analysis Novel Genes Associated with Familial PD. The functional consequences of identified mutations will be evaluated though the use of several model systems. The pathogenic effect of the mutations in induced pluripotent stem cells, Drosophila and yeast models will be studied using established assays. These studies may identify additional genes and pathways that have direct relevance to the development of PD. We are confident that the proposed project will lead to the discovery of one or more novel genes associated with PD. The identification of such genes will lead to an increased knowledge of the defects contributing to this devastating disease and open new avenues of research for the PD scientific community as well as the development of new therapeutic targets.