Genetic Associations with Alzheimer-free Survival

遗传与无阿尔茨海默病生存率的关系

• 批准号: 7121597
• 负责人: PATRICIA L KRAMER
• 金额: $ 45.89万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121597
• 关键词: Alzheimer' s disease; Internet; aging; behavioral /social science research tag; biotechnology; cognition; computer system design /evaluation; disease /disorder classification; disease /disorder onset; genetic mapping; genetic markers; genetic registry /resource /referral center; genetic screening; genetic susceptibility; high throughput technology; human genetic material tag; human tissue; microarray technology; neurogenetics; neuropathology; postmortem; single nucleotide polymorphism

DESCRIPTION (provided by applicant): The genetic correlates of survival to advanced age without Alzheimer Disease (AD) are a tractable target for discovery. A large collection of subjects is available who enter Alzheimer Disease Center (ADC) programs non-demented and are then followed through either conversion to AD or maintenance of non-AD clinical status. Longitudinal clinical and neuropsychological data, DMA and/or brain tissue and neuropathological data exist for many of these individuals. This resource, along with high-throughput SNP (single nucleotide polymorphism) genotyping technology, provides a unique opportunity for identifying genetic variations associated with AD-free survival. We have identified approximately 300 autopsy-confirmed AD subjects collected prospectively at eight collaborating ADC sites, and over 400 deceased subjects of advanced age with no clinical manifestation of dementia just prior to death ("non-demented"). We will generate > .100,000 genome-wide SNP genotypes for each of these subjects, using the Affymetrix GeneChip(r) Mapping 100K SNP Assay. We will then conduct a genome-wide, case-control SNP association study, using "set association" methods, to identify genetic variants related to delay in age at onset of dementia. In addition, based on autopsy data, we will assign the non-demented subjects to one of three categories of pathological status (low, intermediate or high) representing the likelihood of neuropathological processes leading to AD (NIA/Reagan criteria). Using the genome-wide SNP genotype data generated for these subjects, we will conduct a case-control SNP association study, as in specific aim 1, to identify genetic variants related to maintenance of cognitive function in the presence of neuropathological damage. In collaboration with the National Alzheimer's Coordinating Center (NACC), we will develop a SNP database registry for the 700+ subjects in this study, designed with a web-based, graphical user interface with customized options for data queries and reports. These data will be available primarily through the NACC website for dissemination to the AD and aging research community. Access will also be available through the OHSU ADC Genetics Core.

描述（由申请人提供）：没有阿尔茨海默病（AD）的高龄生存的遗传相关性是一个易于发现的目标。大量受试者以非痴呆状态进入阿尔茨海默病中心 (ADC) 项目，然后跟踪其转变为 AD 或维持非 AD 临床状态。其中许多人都存在纵向临床和神经心理学数据、DMA 和/或脑组织和神经病理学数据。该资源与高通量 SNP（单核苷酸多态性）基因分型技术一起，为识别与无 AD 生存相关的遗传变异提供了独特的机会。 我们已经确定了在 8 个 ADC 合作中心前瞻性收集的大约 300 名尸检确认的 AD 受试者，以及 400 多名在死亡前没有痴呆临床表现的高龄死亡受试者（“非痴呆”）。我们将使用 Affymetrix GeneChip(r) Mapping 100K SNP Assay 为每个受试者生成 > 0.100,000 个全基因组 SNP 基因型。然后，我们将使用“集合关联”方法进行全基因组病例对照 SNP 关联研究，以确定与痴呆症发病年龄延迟相关的遗传变异。 此外，根据尸检数据，我们将把非痴呆受试者分配到三类病理状态（低、中或高）之一，代表神经病理过程导致 AD 的可能性（NIA/里根标准）。利用为这些受试者生成的全基因组 SNP 基因型数据，我们将进行病例对照 SNP 关联研究，如具体目标 1 所示，以确定与神经病理损伤存在下认知功能维持相关的遗传变异。 我们将与国家阿尔茨海默病协调中心 (NACC) 合作，为本研究中的 700 多名受试者开发一个 SNP 数据库注册表，该数据库注册表设计有基于网络的图形用户界面，具有数据查询和报告的定制选项。这些数据将主要通过 NACC 网站提供，并分发给 AD 和老龄化研究界。还可以通过 OHSU ADC 遗传学核心进行访问。