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: 6533735
• 负责人: BRENDA L PLASSMAN
• 金额: $ 98.33万
• 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/6533735
• 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《调查人员摘要》)美国国家科学院 科学/国家研究理事会双胞胎登记处(“登记处”)包含 大约4300对活着的白人男性双胞胎，年龄在72-83岁之间 2000年。这项相互竞争的续期申请建议在登记处进行研究， 结合到目前为止的工作，将产生240对双胞胎，其中一对或两者都有 成员患有阿尔茨海默病(AD)。这一基于人口的小组将启用 继续调查四个主要目标：1)估计 对比研究遗传因素对阿尔茨海默病发病和发病年龄的影响 单合子(MZ)和单合子(MZ)内的符合率和起始集的相似性 双合子(DZ)对；2)表征环境贡献 阿尔茨海默病发病的变异性。例如，在MZ对内的起始点的可变性 定义环境影响可以修改的最大程度 AD的发病；3)评估特定基因在发育和年龄中的作用 使用兄弟姐妹传递/不平衡检验方法研究AD的发病 研究阿尔法-2等候选基因之间的关联 巨球蛋白(A2M)和AD；以及4)确定环境因素 与阿尔茨海默病的风险相关，使用同卵双胞胎控制方法。 这项研究将利用阿尔茨海默病遗传学的最新发展， 载脂蛋白E(APOE)基因和候选基因对载脂蛋白E的影响 A2M基因对阿尔茨海默病易感性及其发病时机的影响。这样的发现可以是 用于提炼经典的孪生范式调查BRED(但是 异质性)遗传和环境影响。因此，人们不仅可以 一般估计AD的遗传度，但也进行分区 APOE基因分型的表型变异估计分析 或其他标记系统，因为这些是被识别的。然而，直到所有的 识别出易患阿尔茨海默病的基因，双胞胎方法有几个 与其他方法相比，在确定遗传和基因突变的程度方面具有优势 环境对AD的贡献。 几个MZ孪生对已被描述为AD的大相径庭的首字母组。 因此，环境因素可能会改变发病，从而改变种群 风险，一些遗传定义的AD形式。这项研究将分析 环境对发病变异性的贡献，并将成为 几组基因匹配的个体之间的发病差异。自.以来 关于环境因素的全面信息已收集到所有 作为孪生姐妹登记处的参与成员，本研究还将采用 共双生子控制法寻找可能存在的特定环境因素 对这一变化负有责任。基于人口的双胞胎设计仍然是 这类调查的理想方法。