Additional Sequencing for the Alzheimer's Disease Sequencing Project (ADSP)

项目摘要 阿尔茨海默病（AD）是老年痴呆症的主要原因，发生在所有种族和种族群体中。 AD中的大量遗传研究已经鉴定了多种AD相关基因和位点，但是大部分AD相关基因和位点都是由基因组中的一个或多个决定的。 AD的遗传贡献仍然未知。阿尔茨海默病测序项目（ADSP）正在使用 大规模的测序工作，以增加我们对影响AD的遗传变异的了解， 特别是罕见的遗传变异，增加AD风险或预防AD。在最近的一波融资中， ADSP正在对来自ADSP随访研究（FUS）至AG 057659和AG 062943的个体进行测序。 这些努力是专门设计来改善ADSP数据集中的种族和民族多样性，以及 获得独特而强大的数据集，用于NHW个体的基因发现，例如Amish保护性基因， 变异（Vdd HPV）数据集，几个大型尸检证实的系列和ADGC的早发性AD数据集。 这些研究的目的是利用遗传背景的差异， 确定新的保护性和风险位点，并最终解决AD和相关疾病的健康差异 服务不足人群的疾病。包括本申请中的队列，ADSP-FUS将执行WGS 近3万人身上。该应用程序的一个额外好处是高质量的加工和交付 本申请中新队列的WGS和表型数据。具体而言，我们建议：（1）增加 通过纳入约1900例AD病例，进一步丰富ADSP的临床表型数据， 来自阿尔茨海默病中心（ADC）西班牙裔队列的对照，来自法罗群岛的约1500例AD病例和对照 岛，以及来自特征良好的种族多样性A4临床试验队列的约3，200例AD病例和对照; (2)与阿尔茨海默病国家细胞库（NCRAD）密切合作，组装DNA， 这些现有队列的血液最终将作为阿尔茨海默病的中心资源， （3）使用WGS技术为所有收集的样品生成全基因组SNP阵列数据和WGS数据。 （4）与NIAGADS、GCAD和HIHG CGESG-PGNC QC团队合作， 处理、存储并向NIAGADS交付最终数据集，以发布公共数据;以及（5）协调临床 来自新获取和现有FUS数据集的数据，以生成高质量的推理等效表型 和内表型。该项目将把几个新的群组合并到ADSP-FUS中，以进一步加强 ADSP是阿尔茨海默病（AD）研究社区的宝贵资源。这些努力将加快 为所有人群发现AD诊断、预防和治疗的靶点。

PROJECT SUMMARY Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. A multitude of genetic studies in AD have identified multiple AD associated genes and loci, but a large portion of the genetic contribution to AD remains unknown. The Alzheimer Disease Sequencing Project (ADSP) is using large-scale sequencing efforts to increase our knowledge about the genetic variation that influences AD, particularly rare genetic variants that enhance AD risk or protect against AD. In the most recent wave of funding, the ADSP is sequencing individuals from the ADSP Follow-up Study (FUS) through AG057659 and AG062943. These efforts were specifically designed to improve racial and ethnic diversity in the ADSP datasets as well as to acquire unique and powerful data sets for gene discovery in NHW individuals, such as the Amish protective variant (AMISHPV) dataset, several large autopsy-confirmed series and the ADGC's early-onset AD dataset. The purpose of these studies has been to capitalize on differences in genetic backgrounds that may facilitate the identification of new protective and risk loci and ultimately address health disparities for AD and related disorders in underserved populations. Including the cohorts in this application, the ADSP-FUS will perform WGS on nearly 30,000 individuals. An added benefit of this application is the processing and delivery of high quality WGS and phenotype data on the new cohorts in this application. Specifically we propose to: (1) Increase the diversity and further enrich the clinical phenotype data of the ADSP through inclusion of ~1900 AD cases and controls from the Alzheimer Disease Center (ADC) Hispanic cohort, ~1500 AD cases and controls from the Faroe Islands, and ~3,200 AD cases and controls from the well characterized ethnically diverse A4 Clinical Trial Cohort; (2) work closely with the National Cell Repository for Alzheimer's Disease (NCRAD) in assembling DNA and blood on these existing cohorts which will ultimately serve as a central resource for the Alzheimer's disease research community; (3) generate genome-wide SNP array data and WGS data for all collected samples using established resources; (4) collaborate with NIAGADS, GCAD and the HIHG CGESG-PGNC QC Teams in processing, storage, and delivery of final datasets to NIAGADS for public data release; and (5) harmonize clinical data from newly acquired and existing FUS datasets to generate high quality inferentially equivalent phenotypes and endophenotypes. This project will merge several new cohorts into the ADSP-FUS to further enhance the ADSP as an invaluable resource for the Alzheimer's disease (AD) research community. These efforts will speed discoveries of targets for AD diagnosis, prevention, and treatment for all populations.