Alzheimer's Disease Genetics Consortium

 描述（由申请人提供）：本提案描述了阿尔茨海默病遗传学联盟（ADGC）的未来工作。目的是解构阿尔茨海默病（AD）的完整遗传结构，并确定所有遗传因素如何促成AD表型。为此，我们将识别、注释、复制和验证所有 增加风险或预防AD的DNA变异，确定哪些基因与这些变异相关，并评估每种变异对总AD风险的贡献。以下遗传学/基因组学项目的基本原理是：1）预测谁将发展AD。2)充分揭示所有种族人群的所有AD遗传学。3)了解AD的发病机制。4)确定AD的新治疗靶点。因此，我们将使用不仅利用基因分型阵列而且利用大规模平行DNA序列方法的数据的方法来鉴定AD的新基因/治疗靶点。由于我们对AD遗传学的了解大部分来自高加索人AD研究，因此我们将不仅关注高加索人，而且关注非洲裔美国人，拉丁美洲人和亚洲人。为了解决AD遗传学问题，我们将：在AIM 1中，使用功能基因组学来识别AD风险和顺式作用调节元件中的保护性变体， 并确定受这些克雷斯影响的基因;在AIM 2中，我们将使用计算机系统生物学方法整合所有AD基因的信息，以确定与AD相关的相互作用网络和途径;在AIM 3中，我们将使用基于基因（包括克雷斯）的分析来确定其他AD罕见变异基因。所有种族群体将通过这些方法进行分析;在AIM 4中，我们将对非裔美国人受试者进行全外显子组测序，以概括高加索人的发现，完善基因定位，识别新的变异，并识别仅在其他种族群体中发现的新基因。随后将在非洲裔美国人和拉丁美洲人中进行靶向测序;在AIM 5中，我们将组装和协调多个队列中可用的表型，以识别AD亚型和与这些亚型相关的变异体相关的基因。

 DESCRIPTION (provided by applicant): This proposal describes future work of the Alzheimer's Disease Genetics Consortium (ADGC). The goal is to deconstruct the complete genetic architecture of Alzheimer's disease (AD), and to determine how all inherited factors contribute to the AD phenotype. To this end we will identify, annotate, replicate, and validate all DNA variants that increase risk or protect against AD, determine what genes are connected to these variants, and evaluate the contribution of each to total AD risk. The rationale for the following genetics/genomics project is to: 1) Predict who will develop AD. 2) Fully reveal all AD genetics in all ethnic groups. 3) Understand the pathogenesis of AD. 4) Identify novel therapeutic targets for AD. Therefore, we will identify new genes/therapeutic targets for AD using methods that make use of data from not only genotyping arrays but also massively parallel DNA sequence approaches. Because much of what we know about AD genetics comes from Caucasians AD studies, we will focus future analysis on not only Caucasians but also on African Americans, Latinos, and Asians. To resolve AD genetics, we will: in AIM 1, use functional genomics to identify AD risk and protective variants in cis- acting regulatory elements, and identifying the genes affected by these CREs; in AIM 2, we will use in silico systems biology approaches to integrate information from all AD genes to identify interaction networks and pathways relevant to AD; in AIM 3, we will identify additional AD rare-variant genes using gene-based (including CREs) analyses. All ethnic groups will be analyzed by these methods; in AIM 4, we will perform whole exome sequencing on African American subjects to generalize findings made on Caucasians, to refine gene localization, to identify novel variants, and to identify novel genes found only in other ethnic groups. This will be followed up by targeted sequencing in African Americans and Latinos; in AIM 5 we will assemble and harmonize phenotypes available in multiple cohorts to identify subtypes of AD and genes associated with variants associated with those subtypes.