The Alzheimer Disease Sequence Analysis Collaborative

阿尔茨海默病序列分析协作组织

• 批准号: 9788240
• 负责人: William S Bush
• 金额: $ 292.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788240
• 关键词: 3-Dimensional; Admixture; Affect; African American; Alzheimer disease prevention; Alzheimer' s Disease; Attention; Awareness; Biological; Case Study; Cholesterol Homeostasis; Code; Cohort Studies; Collaborations; Computer Simulation; Data; Data Analyses; Data Set; Dementia; Development; Emotional; Endocytosis; Ethnic Origin; European; Family Study; Financial Hardship; Follow-Up Studies; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic screening method; Genomics; Goals; Hispanic Americans; Hispanics; Individual; Late Onset Alzheimer Disease; Location; Meta-Analysis; Methylation; Minority; Mitochondria; Modification; Native Americans; Not Hispanic or Latino; Pathway Analysis; Pathway interactions; Phase; Population; Proteins; Research; Research Design; Risk; SNP array; Sampling; Sequence Analysis; Signal Transduction; Societies; Structural Genes; Structure; Testing; Treatment Efficacy; Variant; X Chromosome; admixture mapping; amyloid precursor protein processing; base; case control; epigenomics; ethnic diversity; exome sequencing; genetic variant; genome sequencing; genomic data; genomic variation; insertion/deletion mutation; loss of function; neuroinflammation; novel; rare variant; sex; targeted treatment; therapeutic development; therapeutic target; therapy development; trait; whole genome

The Alzheimer's Disease Sequencing Project (ADSP) is a national sequencing initiative focused on identifying genetic variants that either protect from or increase the risk for late onset Alzheimer Disease (LOAD), with the goal of accelerating development of effective therapeutics. The ADSP Discovery phase includes whole exome sequencing (WES) of 10,571 unrelated non-Hispanic White (NHW) cases (N=5,606) and controls (N=4,965), and whole genome sequencing (WGS) of 578 NHW and Hispanic (HI) familial samples. The Discovery Extension Phase of the project added WGS on 434 new familial samples and 3,343 NHW, AA, and HI cases and controls (collectively the ADSP-DEP). Preliminary analyses of these data confirm known LOAD genes and point toward several new LOAD-related genes and their functional relationships to APP processing, neuroinflammation, endocytosis, and cholesterol metabolism. The current Follow-Up Study phase (ADSP-FUS) will generate >15,000 additional WGS focused on samples that `encompass the richest possible ethnic diversity', which will include primarily HI and African-American (AA) datasets. This combination of diverse datasets derived from case-control, cohort, and family study designs requires an intensive and comprehensive analytical effort to uncover the wealth of information sequestered in the WGS. We (the Collaboration on Alzheimer Disease REsearch [CADRE]) hypothesize that protective and risk genomic variants will provide potential therapeutic targets for Alzheimer disease. Thus, the primary goal of this proposal is to integrate comprehensive genomic analysis of the combined ADSP data (WGS, WES, SNP array) with extant biological data to identify the highest priority variants and loci as candidates for downstream functional analysis. By leveraging the data derived from the AA and HI admixed populations, we use their increased diversity to accelerate and define likely targets. This goal will be met by: 1) Characterizing genomic variation in LOAD using ethnically diverse datasets. We will supplement the ADSP-DEP and ADSP-FUS with additional, separately funded WES and WGS data; 2) enhancing discovery and fine-mapping using admixture analyses in ethnically diverse datasets; and 3) Prioritizing variants and genes by integrating statistical and biological information. For the variants we identify, we will generate additional information from structural and gene expression data and integrate all data into a genomically driven comprehensive biological network that will be used to prioritize loci for functional testing as therapeutic targets.

阿尔茨海默病测序项目 (ADSP) 是一项国家测序计划，专注于识别 可以预防或增加晚发性阿尔茨海默病 (LOAD) 风险的基因变异，其中 加速开发有效疗法的目标。 ADSP Discovery 阶段包括整个外显子组 对 10,571 名不相关的非西班牙裔白人 (NHW) 病例 (N=5,606) 和对照 (N=4,965) 进行测序 (WES)， 以及 578 个 NHW 和西班牙裔 (HI) 家族样本的全基因组测序 (WGS)。发现扩展 该项目阶段增加了对 434 个新家族样本和 3,343 个 NHW、AA 和 HI 病例和对照的全基因组测序 (WGS) （统称为 ADSP-DEP）。对这些数据的初步分析证实了已知的 LOAD 基因并指出 几个新的 LOAD 相关基因及其与 APP 处理、神经炎症、 内吞作用和胆固醇代谢。当前的后续研究阶段（ADSP-FUS）将产生 > 15,000 个额外的 WGS 重点关注“包含尽可能丰富的种族多样性”的样本，这将 主要包括 HI 和非裔美国人 (AA) 数据集。这种来自不同数据集的组合 病例对照、队列和家庭研究设计需要深入而全面的分析工作 揭示 WGS 中隐藏的大量信息。我们（阿尔茨海默病合作组织 研究 [CADRE]）假设保护性和风险基因组变异将提供潜在的治疗 阿尔茨海默病的目标。因此，本提案的主要目标是整合全面的 将 ADSP 数据（WGS、WES、SNP 阵列）与现有生物数据相结合进行基因组分析 确定最高优先级的变体和基因座作为下游功能分析的候选者。经过 利用来自 AA 和 HI 混合群体的数据，我们利用其增加的多样性来 加速并确定可能的目标。该目标将通过以下方式实现：1) 使用以下方法表征 LOAD 中的基因组变异： 种族多样化的数据集。我们将单独补充 ADSP-DEP 和 ADSP-FUS 资助 WES 和 WGS 数据； 2）利用种族混合分析增强发现和精细绘图 多样化的数据集； 3) 通过整合统计和生物信息来确定变体和基因的优先顺序。为了 我们识别出的变异，我们将从结构和基因表达数据中生成额外的信息， 将所有数据整合到基因组驱动的综合生物网络中，用于确定基因座的优先级 作为治疗目标的功能测试。