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

基本信息

批准号：
10242839
负责人：
RICHARD P MAYEUX
金额：
$ 462.64万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242839
关键词：
Address African African American Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Americas Case-Control Studies 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 cell repository 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 large datasets new therapeutic target novel protective allele protective factors repository risk variant screening whole genome working group

项目摘要

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.

项目摘要阿尔茨海默氏病测序项目（ADSP）是一项针对的国家测序计划确定阿尔茨海默氏病（AD）的遗传风险和受保护因素，以识别新途径用于预防和药物开发的新目标。项目的发现阶段包括整个外显者测序（WES）为10,914例无关病例（n = 5,778）和对照（n = 5,136）和整个基因组测序 1,019个家族样本的（WGS）。这些样本中的大多数是非西班牙裔白人（NHW），使得将种族多元化的样本添加到研究至关重要的研究至关重要的研究中人群之间的广告风险因素。 “ ADSP随访研究”强调了这种种族多样性（FUS）阶段的规划阶段，并带有指令，该指令与无关的AD案件进行了其他现有同类 “涵盖最富有的种族多样性”是包容性的最高优先事项。为了实现此RFA和该FUS阶段任务的目标，该提案较早地确定了七个现有非裔美国人（AA）和Pan-Hi血统共有10,430个样本（n = 2,322 AA AD病例）以及1,843个AA控件和2,928个西班牙裔AD案例和2,875个西班牙裔控制），用于WGS和处理与现有NIH资助的广告基础架构的合作。将这些队列与现有的非洲美国人相结合（AA）和西班牙裔（HI）测序来自华盛顿高地 - 哈米尔顿高地社区社区老化项目（WHICAP），阿尔茨海默氏病遗传学财团（ADGC）和ADSP将提供大量种族多元化的数据集用于验证ADSP发现阶段发现和发现新风险的数据集和/或AD的受保护变体。重要的是，这些数据将允许进行混合映射，这是一种强大的方法通过比较等位基因频率差异来显示出祖先显示差异风险的疾病的基因映射人口之间。它们还将成为广告研究社区一般的宝贵资源，并将有助于解决有助于AA和HI人群的健康分布比NHW。这是，我们将通过创建大型AA和Pan-Hi AD案例来解决这些重要问题和研究控制。具体我们建议：1）通过组装样本中的样本来增加ADSP的种族多样性现有的与AA和HI AD案件和对照组的队列； 2）与国家单元存储库合作阿尔茨海默氏病（NCRAD）在这些队列上DNA的组合，存储和分布中； 3）生成所有收集样品的全基因组SNP阵列数据和WGS； 4）与NIA遗传学合作阿尔茨海默氏病数据存储现场（Niagads）和阿尔茨海默氏病基因组中心（GCAD）在处理中，最终数据集的质量控制，存储和分布。我们的总体目标是增强通过支持种族多元化数据集中的AD研究来发现AD风险因素。