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

项目总结 阿尔茨海默病(AD)是导致老年人痴呆的主要原因，在所有人种和种族中都会发生。 大量关于AD的遗传学研究已经确定了多个AD相关基因和基因座，但很大一部分 阿尔茨海默病的遗传因素仍不清楚。阿尔茨海默病测序项目(ADSP)正在使用 大规模测序工作，以增加我们对影响AD的遗传变异的了解， 尤其是增加AD风险或预防AD的罕见基因变异。在最近一波融资浪潮中， ADSP正在对从ADSP后续研究(FUS)到AG057659和AG062943的个体进行测序。 这些努力是专门为改善ADSP数据集的种族和族裔多样性而设计的，以及 获取独特和强大的数据集，用于nhw个体的基因发现，例如阿米什保护性基因 变异(阿米西比HPV)数据集，几个大型尸检确认系列和ADGC的早发性AD数据集。 这些研究的目的一直是利用遗传背景的差异，这可能有助于 识别新的保护性和危险基因，并最终解决AD和相关疾病的健康差异 服务不足人群中的疾病。包括此应用程序中的队列，ADSP-FUS将执行WGS 在近30,000个人身上。此应用程序的另一个好处是高质量的处理和交付 这一应用中新队列的WGS和表型数据。具体来说，我们建议：(1)增加 通过纳入约1900例AD患者，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，约1500例AD病例和来自Faroe的对照 岛屿，约3,200例AD病例和来自具有良好种族多样性的A4临床试验队列的对照； (2)与阿尔茨海默病国家细胞库(NCRAD)密切合作，组装DNA和 这些现有队列上的血液最终将成为阿尔茨海默病的主要来源 研究社区；(3)为所有收集的样本生成全基因组SNP阵列数据和WGS数据 建立资源；(4)与NIAGADS、GCAD和高级别CGESG-PGNC QC团队在 处理、存储最终数据集并将其交付给NIAGADS以发布公共数据；以及(5)协调临床 来自新获得的和现有的FUS数据集的数据，以生成高质量的推断等价的表型 和内表型。该项目将把几个新的群体合并到ADSP-FUS中，以进一步增强 ADSP是阿尔茨海默病(AD)研究界的宝贵资源。这些努力将加快 发现适用于所有人群的AD诊断、预防和治疗靶点。

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.