Additional Sequencing Cohorts for the Alzheimer's Disease Sequencing Project

项目总结 阿尔茨海默氏症测序项目(ADSP)是一项全国性的测序计划，重点是 确定阿尔茨海默病的遗传风险和保护因素。项目的发现阶段包括整个exome 对10,061例无关的非白人西班牙裔(NHW)病例(N=5,096)和对照(N=4,965)进行了测序(WES)， 以及584个nhw和西班牙裔家庭样本的全基因组测序(WGS)。‘Discovery扩展 该项目的‘阶段’在大约430个额外的家庭样本上增加了WGS。初步的“后续研究(FUS)” 阶段侧重于检查发现阶段的候选变体，并识别新的变体 通过对不同数据集的组合分析正在进行中，并专注于其他现有队列 无关的AD病例包含了最丰富的种族多样性以及极具价值的一系列 尸检确认病例和对照。我们总共已经在FUS中包括了14000多个样品 测序包括2800例尸检确诊病例和对照、6800例西班牙裔(HI)病例和对照 和5790例非裔美国人(AA)病例和对照。在这个FUS2应用程序中，我们建议进行排序 额外的4243个样本，这既会增加我们发现效果的能力，也会增强我们的 通过包含几个丰富而独特的样本集进行分析。此外，这些数据集将成为 对于整个AD研究社区来说，这是非常宝贵的资源。 总而言之，ADSP将为这两个民族提供大量不同种族的唯一数据集 验证和推广ADSP发现阶段的结果，并发现新的风险和 晚发性AD的保护性变异体/基因(LOAD)。此外，这些数据集将成为无价的 为AD研究社区提供的资源。具体来说，我们建议：1.增加多样性和 进一步丰富ADSP的临床表型数据，包括有针对性地发现保护作用的数据集 通过从实现这一目标的独特种群的现有队列中收集样本。2. 与国家阿尔茨海默病细胞库(NCRAD)合作，在 这些现有的队列，将作为AD研究界的中心资源。3.生成 约翰·P·赫斯曼研究所(HIHG)基因组中心提供的全基因组SNP阵列数据 技术(CGT)和全基因组测序数据，通过统一服务大学 所有收集的样本的健康科学(USUHS)4.与AD数据存储的NIA Genetics合作 网站(NIAGADS)，AD基因组中心(GCAD)和宾夕法尼亚大学和HiHG 遗传流行病学和统计遗传学质量控制小组在加工、储存和 最终数据集的传播。我们的总体目标是加强AD风险的发现和预防 通过促进种族多样性和表型丰富的数据集对阿尔茨海默病的研究。

PROJECT SUMMARY The Alzheimer's Disease Sequencing Project (ADSP) is a national sequencing initiative focused on identifying genetic risk and protective factors for AD. The projects' discovery phase includes whole exome sequencing (WES) of 10,061 unrelated non-White Hispanic (NHW) cases (N=5,096) and controls (N=4,965), and whole genome sequencing (WGS) of 584 NHW and Hispanic familial samples. The 'Discovery Extension Phase' of the project added WGS on ~430 additional familial samples. An initial 'Follow-Up Study (FUS)' Phase focused on examining candidate variants from the discovery phase, and identification of novel variants through combined analysis of diverse datasets is ongoing and focuses on additional existing cohorts with unrelated AD cases that 'encompass the richest possible ethnic diversity' as well as highly valuable set of autopsy confirmed cases and controls. In total we have already included in FUS over 14000 samples for sequencing including >2800 autopsy confirmed cases and controls, >6800 Hispanic (HI) cases and controls and > 5790 African American (AA) cases and controls. In this FUS2 application, we are proposing sequencing of an additional 4243 samples that will both increase our power to find effects but will also enhance our analysis by inclusion of several rich and unique sample sets. Additionally, these datasets will become an invaluable resource for the AD research community at-large. In summary ADSP will provide large ethnically diverse as well as unique datasets for both validation and generalization of ADSP discovery phase findings and discovery of novel risk and protective variants/genes for late onset AD (LOAD). Additionally, these datasets will become an invaluable resource for the AD research community at-large. Specifically we propose to: 1. Increase the diversity and further enrich the clinical phenotype data of the ADSP including data sets targeted to find protective effects through assembling samples from existing cohorts from unique populations that fulfill this goal. 2. Collaborate with the National Cell Repository for AD (NCRAD) in assembling DNA, blood and brain tissue on these existing cohorts, which will serve as a central resource for the AD research community. 3. Generate genome-wide SNP array data through the John P. Hussman Institute (HIHG) Center for Genome Technology (CGT) and whole genome sequencing data through the Uniformed Services University of the Health Sciences (USUHS) for all collected samples 4. Collaborate with NIA Genetics of AD Data Storage Site (NIAGADS), the Genome Center for AD (GCAD) and the University of Pennsylvania and the HIHG Center for Genetic Epidemiology and Statistical Genetics Quality Control Teams in processing, storage and dissemination of final data sets. Our overall goal is to enhance the discovery of AD risk and protective factors by facilitating research on AD in ethnically diverse and phenotypically rich datasets.