Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches

通过结合种族多样性和系统方法的全面全基因组分析，在 ADSP 数据中发现治疗靶点

• 批准号: 10683597
• 负责人: ERIC A. BOERWINKLE
• 金额: $ 3.21万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683597
• 关键词: Accounting; Admixture; African American; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Bioinformatics; Biological; Clinical; Clinical Research; Cognition; Cognitive; Collaborations; DNA Methylation; Data; Data Set; Development; Disease; Disease Pathway; Drug Targeting; Elderly; Ensure; Equilibrium; Ethnic Origin; Ethnic group; European; Evaluation; Follow-Up Studies; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Heart; Hispanic Americans; Human Biology; Information Retrieval; Infrastructure; Investments; Magnetic Resonance Imaging; Maps; Measures; Medicine; Meta-Analysis; Methodology; Methods; MicroRNAs; Participant; Pathway interactions; Phase; Phenotype; Population; Population Heterogeneity; Prevention; Procedures; Quality Control; Research; Research Personnel; Resources; Risk; Role; Sampling; Single Nucleotide Polymorphism; Structure; System; Trans-Omics for Precision Medicine; Validation; Variant; Work; admixture mapping; aging brain; bioinformatics network; bioinformatics tool; candidate validation; case control; cohort; endophenotype; ethnic diversity; exome; exome sequencing; experience; gene network; genetic variant; genome analysis; genome sequencing; genome wide association study; genome-wide analysis; genomic epidemiology; innovation; insertion/deletion mutation; member; metabolomics; multi-ethnic; network models; novel; pre-clinical; programs; protective allele; rare variant; risk variant; statistics; therapeutic target; whole genome; working group

Project Summary/Abstract: The Alzheimer Disease Sequencing Project (ADSP) seeks to identify new genomic variants contributing to increased risk for and protection from Alzheimer's Disease in multi-ethnic populations, and to identify new pathways for disease treatment and prevention. Whole genome and whole exome sequencing data (WGS and WES) are available from ADSP Discovery and Discovery-Extension Phases and WGS in diverse ethnic groups will be generated for the Follow-up Study (FUS). The investigators of this proposal have diverse but complementary expertise across the range of bioinformatics, applied statistics and methodological development, admixture and ethnic diversity, rare variant association, network modeling, preclinical validation of targets, and clinical expertise in AD and have been involved in the ADSP since its inception. Further they bring expertise on endophenotypes and additional WGS data through their role within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) and TOPMed (Trans-Omics for Precision Medicine) consortia. We now propose the following aims to meet ADSP goals. Aim 1: To fully characterize known AD loci and to identify novel protective and risk variants for AD by exploiting the full range of genetic variability revealed by WGS including single nucleotide polymorphisms, small insertion/deletions, and structural variants. Analyses will include expanded association analyses of AD and endophenotypes, identification of novel protective variants via carefully selected “Wellderly” samples, and integration of findings across analyses. Aim 2: To leverage ethnically-diverse and admixed populations to identify novel variants for AD and endophenotypes. This will be achieved by estimating and accounting for global-scale population structure in association analyses across the three phases of ADSP. We additionally propose to perform admixture mapping in samples of admixed ancestry and to perform ethnic-specific analyses and trans-ethnic meta- analyses. Aim 2 analyses will be performed for AD, AD endophenotypes, and Wellderly status. Aim 3: To functionally characterize genes, gene networks, and systems, via bioinformatics and omics integrative analyses to identify putative therapeutic targets. The investigators will work closely with the Accelerating Medicines Partnership (AMP) projects. We propose to use a combination of bioinformatics tools and analysis of “omics” data, including DNA methylation, gene expression, miRNA and metabolomics data within AMP and in the CHARGE cohorts to predict function of specific variants or groups of variants, to apply network approaches across gene sets, to utilize a systems approach to understand the ADSP sequencing data in the larger context of human biology and to identify putative therapeutic targets. Our proposal provides a comprehensive, integrated plan, which we will implement within the existing ADSP infrastructure and in coordination with ADSP investigators.

项目摘要/摘要： 阿尔茨海默氏病测序项目（ADSP）旨在确定有助于 在多种族人群中增加了对阿尔茨海默氏病的风险和保护侵害阿尔茨海默氏病的风险，并确定新的 疾病治疗和预防的途径。全基因组和整个外显子组测序数据（WGS和 WES）可从ADSP发现和发现延伸阶段以及WGS中获得WES） 将生成后续研究（FUS）。该提案的调查人员有多样化，但 在生物信息学，应用统计和方法论范围内的完全专业知识 开发，混合和种族多样性，稀有变体关联，网络建模，临床前验证 自成立以来，目标和AD的临床专业知识一直参与ADSP。进一步 通过其在收费中的角色（队列 用于基因组流行病学的心脏和衰老研究）和最高的（精密医学的跨词） 财团。现在，我们提出以下目标来实现ADSP目标。目标1：完全表征已知的广告基因座 并通过利用各种遗传变异性来识别AD的新型保护和风险变体 由WG揭示，包括单核苷酸多态性，小插入/缺失和结构变体。 分析将包括扩展的AD和内表型的关联分析，新颖的鉴定 通过精心选择的“良好”样本的保护性变体，以及跨分析的发现的整合。目的 2：利用种族多样性和混合种群来识别AD和 内型型。这将通过估计和考虑全球规模的人口结构来实现 协会分析ADSP的三个阶段。我们还建议执行混合 映射杂物的样本并进行特定民族的分析和跨种族的元分析 AIM 2分析将针对AD，AD内表型和良好的状态进行。目标3：到 通过生物信息学和OMICS整合的功能表征基因，基因网络和系统 分析以识别推定的理论目标。调查人员将与加速度紧密合作 药品合作伙伴关系（AMP）项目。我们建议使用生物信息学工具和分析的组合 “幻义”数据，包括AMP和 在预测特定变体或变体组的功能的电荷同时，应用网络 跨基因集的方法，利用系统方法来了解ADSP测序数据 人类生物学的更大背景并确定推定的治疗靶标。我们的建议提供了 全面，集成的计划，我们将在现有的ADSP基础架构中实施 与ADSP研究人员的协调。