Alzheimer Disease Genetic Architecture in African Americans

描述（由申请人提供）：阿尔茨海默病（AD）的一部分遗传成分是通过定位克隆，靶向基因分析和全基因组关联研究确定的基因。除了少数值得注意的例外，这些基因的功能变异和这些变异导致AD的确切致病机制尚不清楚。我们建议将我们的工作重点放在了解非裔美国人（AAs）的AD遗传风险因素上，这是一个痴呆症高发的群体，但AD的遗传结构与欧裔美国人（EAs）不同。最值得注意的是，在AAs中，ABCA7的常见变异对AD风险的影响与APOE相当。我们最近发现了两种罕见的致病性AKAP9突变，它们在AA型AD病例中显著富集，但在ea病例中却不存在，这表明可能存在人群特异性的AD致病变异。我们建议利用我们和AD遗传学协会收集的广泛的临床和遗传资源来鉴定AKAP9、ABCA7和先前鉴定的AD相关基因的功能变异，这些基因直接导致AAs的AD风险。为了实现这一目标，我们将在500个AA AD先证和500个AA年龄匹配的认知正常对照中对这些基因的编码和调控区域进行重排序。将使用生物信息学工具对数据进行评估，以确定可能直接影响AD发病机制的功能变异。潜在的重要功能变异将在发现AA队列和包含1000例病例和2000例对照的复制AA队列中进行相关性测试。我们将尝试在ea中推广这些发现，通过使用公开可用的数据评估排名靠前的变体，以确定在aa中发现的变体是否也是如此

DESCRIPTION (provided by applicant): A portion of the genetic component of Alzheimer disease (AD) is explained genes identified by positional cloning, targeted gene analysis and genome-wide association studies. With few notable exceptions, the functional variants in these genes and precise pathogenic mechanisms by which these variants lead to AD are unknown. We propose to direct our efforts to understanding AD genetic risk factors in African Americans (AAs), a group with a high incidence of dementia but with a different genetic architecture for AD than European Americans (EAs). Most notably, in AAs common variants in ABCA7 has an effect on AD risk comparable to that of APOE. Our recent discovery of two rare pathogenic AKAP9 mutations that are significantly enriched in AA AD cases, but absent in EAs altogether, suggests it is likely that there are population-specific AD-causing variants. We propose to use extensive clinical and genetic resources assembled by us and the AD Genetics Consortium to identify functional variants in AKAP9, ABCA7 and previously identified AD-associated genes that contribute directly to AD risk in AAs. To accomplish this goal we will resequence the coding and regulatory regions of these genes in 500 AA AD probands and 500 AA age-matched cognitively normal controls. Data will be evaluated using bioinformatic tools to identify functional variants that may directly influence AD pathogenesis. Potentially important functional variants will be tested for association in the discovery AA cohort and a replication AA cohort containing 1000 cases and 2000 controls. We will attempt to generalize these findings in EAs by evaluating top-ranked variants using publically available data to determine if variants identified in AAs are also important in EAs. Gene expression and RNA-Seq experiments will be performed in brain tissue from AA and EA cases and controls to identify variants that may regulate transcription of alternative isoforms. The most promising variants in ABCA7 and AKAP9 will be introduced into neuronal cells to evaluate their effects on expression and processing of APP, tau and other important AD markers. Finally, we will confirm the importance of these genes by demonstrating altered expression in neuropathologically confirmed brain specimens from AD cases and controls.