Pleiotropy GWAS of Alzheimer's Disease

阿尔茨海默病的多效性 GWAS

基本信息

批准号：
9349452
负责人：
Adam Christian Naj
金额：
$ 41.13万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2016-09-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9349452
关键词：
Affect Alzheimer&apos s Disease Amyloid beta-Protein Amyotrophic Lateral Sclerosis Archives Biological Biological Markers Brain Candidate Disease Gene Case-Control Studies Cohort Studies Collection Data Data Analyses Data Set Development Disease Enhancers Ethnic group Event Frontotemporal Dementia Genes Genetic Genetic study Genomics Genotype Genotype-Tissue Expression Project Goals Haplotypes Heritability Individual Inflammation Knowledge Lewy Body Dementia Mental Depression Meta-Analysis Methods National Institute on Aging Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Parkinson Disease Pathologic Pathology Pathway Analysis Pathway interactions Persons Phenotype Process Progressive Supranuclear Palsy Prospective cohort study Proteins Protocols documentation Research Personnel Resources Risk Risk Factors Schizophrenia Structure TREM2 gene Testing Time United States National Institutes of Health Validation Variant Work alpha synuclein base case control cohort data resource database of Genotypes and Phenotypes endophenotype exome exome sequencing experience functional genomics genetic association genetic risk factor genetic variant genome wide association study genome-wide genomic data hyperphosphorylated tau improved interest longitudinal analysis neurodegenerative phenotype neuropsychiatric disorder novel online resource phenotypic data pleiotropism protein aggregation rare variant tau Proteins tau aggregation therapeutic target trait whole genome

项目摘要

PROJECT SUMMARY This proposal, entitled “Pleiotropy GWAS of Alzheimer's Disease and Multiple Neurodegenerative Diseases,” describes plans to analyze existing neurodegenerative phenotype and genome-wide genotype data from existing genome-wide association studies (GWAS) of multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD), among others. While neurodegenerative diseases have distinct pathologies, there are also shared pathological features like protein aggregation in the brain (e.g., tau protein). This suggests that genetic studies combining neurodegenerative disease genetics studies may identify genetic risk factors contributing to one or more individual NDs (“pleiotropy”) through these common features. The goal of these planned analyses is to identify genetic loci and variants with effects across multiple NDs. Our approach includes broad hypothesis-free analyses like GWAS meta-analysis, as well as targeted “drill-down” approaches like pathway analyses examining known biological pathways. These analyses will use publicly available data on genome-wide association study and whole genome/exome sequence datasets curated by individual groups, disease-specific consortia, and on the NIH Database of Genotypes and Phenotypes (dbGaP). This project will require extensive collection of genotypes from well-characterized cases and controls; systematic archiving of case-control and prospective cohort studies; a formally-structured data harmonization process; inclusion of multiethnic GWAS and WGS/WES studies; and longitudinal analyses in cohort studies of neurodegeneration in order to fulfill the mandate of the National Institute on Aging (NIA) RFA PAR-15-356. Our three aims include (1) harmonization and integration of genotype and phenotype data from multiple large-scale genetic studies of differeing neurodegenerative diseases; (2) estimating shared heritability between neurodegenerative diseases and performing GWAS and WGS/WES association study meta-analyses; and (3) performing analyses of intermediate and related phenotypes and incorporating functional annotation to identify truly functional pleiotropic variants and their causal effects on multiple neurodegenerative diseases. These analyses will examine both common and rare genomic variants and will use a similar strategy to existing genetic studies comparing neuropsychiatric disorders (e.g, schizophrenia, depression), with refinement and development of novel pleiotropy methods. We will leverage our considerable experience with large-scale genetic association and meta-analysis studies to identify new genetic risk factors for neurodegenerative diseases using data on tens of thousands of affected and unaffected individuals. Furthermore, we will create an online resource for data harmonization and sharing analysis results with investigators interested in shared genetic risk factors of neurodegeneration.

项目概要该提案题为“阿尔茨海默病和多种神经退行性疾病的多效性 GWAS” 描述了分析现有神经退行性表型和全基因组基因型数据的计划现有多种神经退行性疾病的全基因组关联研究（GWAS），包括阿尔茨海默病 (AD)、帕金森病 (PD) 和额颞叶痴呆 (FTD) 等。神经退行性疾病具有独特的病理学，也有共同的病理特征，如蛋白质大脑中的聚集（例如 tau 蛋白）这表明遗传研究结合了神经退行性疾病。疾病遗传学研究可以确定导致一种或多种个体 ND 的遗传风险因素（“多效性”）通过这些共同特征进行这些计划分析的目标是识别遗传位点。以及对多个 ND 产生影响的变体。我们的方法包括广泛的无假设分析，例如 GWAS 荟萃分析，以及有针对性的“深入研究”方法，例如已知的路径检查分析这些分析将使用有关全基因组关联研究和的公开数据。由各个团体、特定疾病联盟以及关于 NIH 基因型和表型数据库 (dbGaP) 该项目需要大量收集数据。来自充分表征的病例和对照的基因型；病例对照和前瞻性的系统归档；队列研究；正式结构化的数据协调流程； WGS/WES 研究；以及神经退行性变队列研究的纵向分析，以实现国家老龄化研究所 (NIA) RFA PAR-15-356 的授权我们的三个目标包括 (1) 协调。以及整合来自不同物种的多个大规模遗传研究的基因型和表型数据 (2) 估计神经退行性疾病和神经退行性疾病之间的共同遗传力进行 GWAS 和 WGS/WES 关联研究荟萃分析；(3) 进行分析；中间和相关表型并结合功能注释来识别真正的功能这些分析将揭示多效性变异及其对多种神经退行性疾病的因果影响。检查常见和罕见的基因组变异，并将使用与现有遗传研究类似的策略比较神经精神疾病（例如精神分裂症、抑郁症），并改进和发展我们将利用我们在大规模遗传关联方面的丰富经验。和荟萃分析研究，利用以下数据确定神经退行性疾病的新遗传风险因素此外，我们将为数万名受影响和未受影响的个人创建一个在线资源。数据协调并与对共同遗传风险因素感兴趣的研究人员共享分析结果神经变性。