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：（改编自调查员的摘要） 科学/国家研究委员会双胞胎注册表（“注册”）包含 大约有4,300对白人双胞胎，年龄为72-83 2000年。这种竞争性更新申请提出了注册表中的研究， 结合迄今为止的工作，将产生240对，其中一对 成员患有阿尔茨海默氏病（AD）。这个基于人群的小组将启用 继续研究四个广泛目标：1）估计 通过对比对AD发育的发展和年龄的遗传影响 一致性率和单卵（MZ）和 dizygotic（DZ）对； 2）表征的环境贡献 AD发作的变异性。例如，MZ对中发作的变异性 定义环境影响可以修改的最大程度 广告发作； 3）评估特定基因在发育和年龄的作用 使用同级传输/不平衡测试方法的AD发作 研究候选基因（例如alpha-2）之间的关联 大球蛋白（A2M）和AD； 4）确定环境因素 使用联合控制方法与开发AD的风险相关。 该研究将利用广告遗传学的最新发展， 特别是载脂蛋白E（APOE）基因型和候选者的影响 基因A2M对AD的责任及其发作时间。这样的发现可以是 用于完善研究广泛的经典双胞胎范式（但 异质）遗传和环境影响。因此，不仅可以 总体上估计广告的遗传力，但也进行了分区 分析以估计可归因于APOE基因型的表型差异 或其他标记系统，因为这些系统已确定。但是，直到所有 鉴定出易于AD的基因，双胞胎方法具有多个 优于确定遗传程度的其他方法的优势 环境对广告的贡献。 已经描述了几对MZ双子对，广泛分歧为AD。 因此，环境因素可能会改变发作，因此种群 风险，某些遗传定义的AD形式。这项研究将分析 环境对发作变异性的贡献，并将表征 遗传匹配个体集合中发作的差异。自从 所有有关环境因素的全面信息已收集 双胞胎注册表的参与成员，本研究还将采用 联合控制方法寻求可能是的特定环境因素 负责这种变化。基于人群的双胞胎设计仍然是 这类调查的理想方法。