PHASE 2 CA GENETIC STUDIES OF ALZHEIMERS DISEASE

阿尔茨海默病(AD)是美国的主要健康问题之一， 随着老年人比例的增加，这一问题变得越来越重要。多重 调查和家庭研究已经显示了遗传成分的证据 与一个主基因一致。这项建议的总体目的是 确定与阿尔茨海默病(AD)相关的基因。作为多个- 由NIMH(精神病诊断中心)资助的中心合作研究 连锁研究)，临床数据和DNA正在400个兄弟姐妹中收集 有多个家族性阿尔茨海默病(FAD)病例。这一努力 代表正在进行的合作的继续，以测试 以下假设：1)单个或交互作用的主效基因 与其他基因一起导致常见形式的FAD：家庭将进行基因分型 在整个过程中以大约10 cM的间隔进行高度多态标记 基因组。这项工作将在三个中心之间进行。运动轨迹 报告的重要性，如与19q的连锁在患有老年患者的家庭中 发病年龄较早的家庭的发病年龄和14号染色体 将被优先排序，以确定这些基因在 我们的家庭(82%)发病年龄超过65岁)。此外, 将对家庭进行淀粉样β蛋白已知突变的筛查 21号染色体上的前体基因；2)FAD是一种遗传异质性 无序：为了最大限度地提高我们检测连锁和异质性的能力， 链接数据将使用标准似然技术进行分析 年龄相关的外显性以及兄弟姐妹和受影响的家系成员 不需要了解特定模式的方法 继承。将进行计算机模拟以确定最好的 应采用的分析策略；3)一旦有证据表明存在关联 获得了额外的高度多态的标记和候选基因 将对染色体区域进行分型。我们的实验室将开发出更多 根据需要在感兴趣的区域中进行高度多态标记。三 各中心将在该项目中进行合作；数据将定期交换 此外，类似的技术也将用于基因分型和数据分析。

Alzheimer's disease (AD) is one of the major health problems in the US and of increasing importance as the proportion of elderly increases. Multiple survey and family studies have shown evidence for a genetic component consistent with a major gene. The overall purpose of this proposal is to identify genes involved in Alzheimer's disease (AD). As part of a multi- center cooperative study funded by NIMH (Diagnostic Centers for Psychiatric Linkage Studies), clinical data and DNA are being collected on 400 sibships with multiple cases of familial Alzheimer's disease (FAD). This effort represents a continuation of the ongoing collaboration to test the following hypotheses: 1) A major gene either singularly or interacting with other genes cause the common forms of FAD: Families will be genotyped for highly polymorphic markers at approximately 10cM intervals throughout the genome. This work will be divided between the 3 centers. Loci of reported significance such as the linkage to 19q in families with an older age-of-onset and chromosome 14 in families with an earlier age-of-onset will be prioritized in order to determine the importance of these genes in our families (82%) with age-of-onset greater than 65 years). In addition, families will be screened for known mutations in the amyloid beta protein precursor gene on chromosome 21; 2) FAD is a genetically heterogeneous disorder: To maximize our power to detect linkage and heterogeneity, linkage data will be analyzed using standard likelihood techniques with age-dependent penetrance as well as sib-pair and affected pedigree member approaches which do not require knowledge of a specific mode of inheritance. Computer simulations will be performed to determine the best analytic strategy that should be employed; 3) Once evidence for linkage is obtained, additional highly polymorphic markers and candidate genes in that chromosomal region will be typed. Our laboratories will develop additional highly polymorphic markers in regions of interest as required. Three centers will collaborate in this project; data will be routinely exchanged and, similar techniques will be used for genotyping and data analysis.