Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS)

ADSP 后续研究 (FUS) 中不同种族群体的全基因组测序

• 批准号: 9757653
• 负责人: RICHARD P MAYEUX
• 金额: $ 195.52万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757653
• 关键词: Address; African; African American; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Americas; Case-Control Studies; Cells; Chromosome Mapping; Clinical Data; Collaborations; Communities; DNA; Data; Data Set; Data Storage and Retrieval; Disease; Elderly; Follow-Up Studies; Funding; Gene Frequency; Genetic; Genetic Diseases; Genetic Risk; Genome; Genotype; Goals; Health; Hispanics; Individual; Infrastructure; Institutes; Late Onset Alzheimer Disease; Methods; Mexican; Multi-Ethnic Study of Atherosclerosis; National Institute on Aging; New York; Not Hispanic or Latino; Participant; Pathway interactions; Phase; Phenotype; Population; Prevention; Production; Puerto Rican; Quality Control; Reasons for Geographic And Racial Differences in Stroke; Research; Resources; Risk; Risk Factors; SNP array; Sampling; Site; Technology; United States National Institutes of Health; Universities; Validation; Variant; Washington; adjudicate; admixture mapping; case control; cohort; database of Genotypes and Phenotypes; drug development; ethnic diversity; exome sequencing; genetic risk factor; genetic variant; genome sequencing; genome-wide; health disparity; human genomics; new therapeutic target; novel; protective factors; repository; screening; whole genome; working group

PROJECT SUMMARY The Alzheimer’s Disease Sequencing Project (ADSP) is a national sequencing initiative focused on identifying genetic risk and protective factors for Alzheimer’s Disease (AD) in an effort to identify new pathways for prevention and new targets for drug development. The projects’ discovery phase included whole exome sequencing (WES) of 10,914 unrelated cases (N=5,778) and controls (N=5,136) and whole genome sequencing (WGS) of 1,019 familial samples. A majority of these samples are non-Hispanic white (NHW) in origin, making the addition of ethnically diverse samples to the study critical to identification of both shared and novel genetic risk factors for AD between populations. This ethnic diversity was emphasized in the ‘ADSP Follow-Up Study (FUS) Phase’ planning stage with a directive that additional existing cohorts with unrelated AD cases that ‘encompass the richest possible ethnic diversity’ be given the highest priority for inclusion. To fulfill the goals of this RFA and this FUS Phase Mandate, this proposal identifies seven existing elderly cohorts of African-American (AA) and pan-HI ancestry with a total of 10,430 samples (N=2,322 AA AD cases and 1,843 AA controls and 2,928 Hispanic AD cases and 2,875 Hispanic controls) for WGS and processing in collaboration with existing NIH-funded AD infrastructure. Combining these cohorts with existing African America (AA) and Hispanic (HI) sequencing from the Washington Heights-Hamilton Heights-Inwood Community Aging Project (WHICAP), the Alzheimer’s Disease Genetics Consortium (ADGC) and the ADSP will provide large ethnically diverse datasets for both validation of ADSP discovery phase findings and discovery of novel risk and/or protective variants for AD. Importantly, these data will allow for admixture mapping, a powerful method of gene mapping for diseases that show differential risk by ancestry, by comparing allele frequency differences between populations. They will also become an invaluable resource for the AD research community at-large, and will help to address the health disparities that contribute to AA and HI populations having higher rates of AD than NHW. Thus, we will address these important issues by creating a large dataset of AA and pan-HI AD cases and controls for study. Specifically we propose to: 1) increase the ethnic diversity of the ADSP by assembling samples from existing cohorts with AA and HI AD cases and controls; 2) collaborate with the National Cell Repository for Alzheimer’s Disease (NCRAD) in assemblage, storage, and distribution of DNA on these cohorts; 3) generating genome-wide SNP array data and WGS for all collected samples; and 4) collaborate with the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) and The Genome Center for Alzheimer’s Disease (GCAD) in processing, quality controls, storage and distribution of the final datasets. Our overall goal is to enhance the discovery of AD risk factors by facilitating research on AD in ethnically diverse datasets.

项目概要 阿尔茨海默病测序项目 (ADSP) 是一项国家测序计划，重点关注 识别阿尔茨海默氏病 (AD) 的遗传风险和保护因素，以找出新的途径 预防和药物开发新目标。该项目的发现阶段包括整个外显子组 对 10,914 个无关病例 (N=5,778) 和对照 (N=5,136) 进行测序 (WES) 以及全基因组测序 (WGS) 1,019 个家族样本。这些样本中的大多数都是非西班牙裔白人 (NHW)，这使得 在研究中添加不同种族的样本对于识别共享和新的遗传至关重要 人群之间 AD 的危险因素。 “ADSP 后续研究”强调了这种种族多样性 (FUS) 阶段的规划阶段，指示添加具有不相关 AD 病例的现有队列， “包容尽可能丰富的种族多样性”被列为包容性的最高优先事项。 为了实现本 RFA 和 FUS 阶段任务的目标，本提案确定了七名现有老年人 非裔美国人 (AA) 和泛 HI 血统队列，共有 10,430 个样本（N=2,322 AA AD 病例 以及 1,843 个 AA 对照和 2,928 个西班牙裔 AD 病例和 2,875 个西班牙裔对照）进行 WGS 和处理 与 NIH 资助的现有 AD 基础设施合作。将这些群体与现有的非裔美国人结合起来 来自 Washington Heights-Hamilton Heights-Inwood 社区老龄化的 (AA) 和西班牙裔 (HI) 测序 项目 (WHICAP)、阿尔茨海默病遗传学联盟 (ADGC) 和 ADSP 将提供大量 种族多样化的数据集，用于验证 ADSP 发现阶段的发现和发现新风险 和/或 AD 的保护性变体。重要的是，这些数据将允许混合映射，这是一种强大的方法 通过比较等位基因频率差异，对显示出不同祖先风险的疾病进行基因定位 人群之间。它们也将成为整个 AD 研究界的宝贵资源， 并将有助于解决导致 AA 和 HI 人群 AD 发病率较高的健康差异 比 NHW 。因此，我们将通过创建 AA 和泛 HI AD 案例的大型数据集来解决这些重要问题 和研究控制。 具体来说，我们建议：1）通过组装来自以下国家的样本来增加 ADSP 的种族多样性： 现有 AA 和 HI AD 病例和对照队列； 2）与国家细胞存储库合作 阿尔茨海默病 (NCRAD) 在这些人群中 DNA 的组装、储存和分布； 3）生成 所有收集样本的全基因组 SNP 阵列数据和全基因组测序 (WGS)； 4) 与 NIA Genetics 合作 阿尔茨海默病数据存储站点 (NIAGADS) 和阿尔茨海默病基因组中心 (GCAD) 最终数据集的处理、质量控制、存储和分发。我们的总体目标是增强 通过促进不同种族数据集中的 AD 研究来发现 AD 风险因素。