Pleiotropy GWAS of Alzheimer's Disease

阿尔茨海默病的多效性 GWAS

• 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
• 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' 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

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.

项目摘要 该提案，标题为“阿尔茨海默氏病和多种神经退行性疾病的多效性GWA”， 描述了分析现有神经退行性表型和全基因组基因型数据数据的计划 现有的全基因组关联研究（GWAS）多种神经退行性疾病，包括 阿尔茨海默氏病（AD），帕金森氏病（PD）和额叶痴呆症（FTD）等。 神经退行性疾病具有不同的病理，也有共同的病理特征，例如蛋白质 大脑中的聚集（例如，tau蛋白）。这表明结合神经退行性的遗传研究 疾病遗传学研究可能鉴定出造成一个或多个个人ND的遗传危险因素 （“多效性”）通过这些共同特征。这些计划分析的目的是确定遗传基因座 以及在多个ND的效果的变体。我们的方法包括广泛的假设分析 GWAS荟萃分析，以及针对性的“钻井”方法，例如检查已知的途径 生物途径。这些分析将使用全基因组协会研究中的公开数据和 由个别群体，疾病特异性财团和在 NIH基因型和表型（DBGAP）的数据库。该项目将需要大量收集 来自特征良好的病例和对照的基因型；案例对照和预期的系统归档 队列研究；正式结构的数据协调过程；包括多民族GWA和 WGS/WES研究；以及神经退行性研究的队列研究中的纵向分析，以实现 国家老化研究所（NIA）RFA PAR-15-356的任务。我们的三个目标包括（1）协调 以及来自多个不同大规模遗传研究的基因型和表型数据的整合 神经退行性疾病； （2）估计神经退行性疾病和 进行GWAS和WGS/WES协会研究荟萃分析； （3）进行分析 中间和相关表型和合并功能注释，以识别真正的功能 多效变体及其因果对多种神经退行性疾病的影响。这些分析将 检查常见和罕见的基因组变体，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），并进行完善和发展 新型多效方法。我们将利用大规模遗传关联的考虑经验 和荟萃分析研究，以鉴定神经退行性疾病的新遗传危险因素使用有关 成千上万的受影响和未受影响的人。此外，我们将为 与对共享遗传风险因素感兴趣的调查人员的数据协调和共享分析结果 神经变性。