GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE IN TWINS

双胞胎阿尔茨海默病的遗传流行病学

• 批准号: 6594651
• 负责人: BRENDA L PLASSMAN
• 金额: $ 9.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594651
• 关键词: Alzheimer's disease; apolipoprotein E; clinical research; disease /disorder etiology; disease /disorder onset; disease /disorder proneness /risk; dizygotic twins; family genetics; gene environment interaction; genetic registry /resource /referral center; genetic susceptibility; human genetic material tag; human old age (65+); human subject; longitudinal human study; low density lipoprotein receptor; macroglobulins; male; monozygotic twins; patient /disease registry; statistics /biometry; twin /multiplet

DESCRIPTION: (Adapted from the Investigator's Abstract) The National Academy of Sciences/National Research Council Twin Registry ("the Registry") contains approximately 4,300 living pairs of white male twins who will be aged 72-83 in 2000. This competing renewal application proposes studies in the Registry that, combined with work to date, will yield 240 twin pairs in which one or both members have Alzheimer's disease (AD). This population-based panel will enable the continued investigation of four broad aims: 1) Estimate the magnitude of genetic influences on the development and age of onset of AD by contrasting concordance rates and the similarity of onsets within monozygotic (MZ) and dizygotic (DZ) pairs; 2) Characterize the environmental contribution of variability of onset of AD. For example, variability of onset within MZ pairs defines the maximum degree to which the environmental influences can modify the onset of AD; 3) Evaluate the role of specific genes on the development and age of onset of AD using the Sibling Transmission/Disequilibrium Test approach to investigate the association between candidate genes such as alpha-2 macroglobulin (A2M) and AD; and 4) Identify environmental factors that are associated with the risk of developing AD, using the co-twin control method. The research will capitalize upon recent developments in the genetics of AD, specifically the influence of apolipoprotein E (APOE) genotype and candidate gene A2M on both liability to AD and its timing of onset. Such findings can be used to refine the classical twin paradigm of investigating broad (but heterogeneous) genetic and environmental influences. Thus, one can not only estimate the heritability of AD in general, but also undertake partitioned analyses to estimate the phenotypic variance attributable to genotypes at APOE or other marker systems, as these are identified. However, until all of the genes that predispose to AD are identified, the twin method has several advantages over other approaches in identifying the extent of the genetic and environmental contribution to AD. Several MZ twin pairs have been described with widely divergent onsets of AD. Environmental factors may therefore alter the onset, and hence the populations risk, of some genetically defined forms of AD. This study will analyze the environmental contribution to variability of onset, and will characterize the divergence in onset within sets of genetically matched individuals. Since comprehensive information on environmental factors has been collected on all participating members of the twin registry, this study will also employ the co-twin control method to seek the specific environmental factors that may be responsible for this variation. A population-based twin design remains the ideal approach to these sorts of investigations.

描述：（改编自研究者的摘要）美国国家科学院 科学/国家研究委员会双胞胎登记处（“登记处”）包含 大约 4,300 对活着的白人男性双胞胎，年龄在 72-83 岁之间 2000. 这项竞争性续展申请建议在登记处进行研究， 结合迄今为止的工作，将产生 240 对双胞胎，其中一对或一对 成员患有阿尔茨海默病（AD）。这个基于人口的小组将使 继续研究四个广泛目标：1）估计 通过对比遗传对 AD 发展和发病年龄的影响 单合子（MZ）和同卵子内起始的一致性率和相似性 双卵（DZ）对； 2) 描述环境贡献 AD 发病的变异性。例如，MZ 对内起始的变异性 定义了环境影响可以改变的最大程度 AD 发作； 3）评估特定基因对发育和年龄的作用 使用兄弟姐妹传递/不平衡测试方法来评估 AD 的发作 研究候选基因（例如 alpha-2）之间的关联 巨球蛋白 (A2M) 和 AD； 4) 确定环境因素 与患 AD 的风险相关，使用双孪生控制方法。 该研究将利用 AD 遗传学的最新进展， 特别是载脂蛋白 E (APOE) 基因型和候选基因的影响 基因 A2M 对 AD 的易感性及其发病时间的影响。这样的发现可以是 用于完善广泛调查（但 异质）遗传和环境影响。这样一来，人们不仅可以 一般估计 AD 的遗传力，但也进行分区 分析估计 APOE 基因型引起的表型变异 或其他标记系统，因为这些已被识别。然而，直到所有 识别出易患 AD 的基因后，孪生方法有以下几种 与其他方法相比，在确定遗传和遗传程度方面具有优势 AD 的环境贡献。 据描述，几对同卵双胞胎的 AD 发病情况差异很大。 因此，环境因素可能会改变发病情况，从而改变人群 某些遗传定义的 AD 形式的风险。本研究将分析 环境对发病变异性的贡献，并将表征 基因匹配的个体中发病的差异。自从 已收集了所有环境因素的综合信息 双胞胎登记处的参与成员，本研究还将采用 共孪生控制方法，寻求可能的特定环境因素 造成这种变化的原因。基于人口的双胞胎设计仍然是 此类调查的理想方法。