Alzheimer Disease Genetic Architecture in African Americans

描述(申请人提供)：阿尔茨海默病(AD)的部分遗传成分被解释为通过位置克隆、靶向基因分析和全基因组关联研究确定的基因。除了几个值得注意的例外，这些基因中的功能变异和导致AD的确切致病机制尚不清楚。我们建议将我们的努力引导到了解非裔美国人(AAs)中的AD遗传风险因素，这是一个痴呆症发病率较高但AD的基因结构与欧洲裔美国人(EAs)不同的群体。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。我们最近发现了两个罕见的致病AKAP9突变，这两个突变在AA AD病例中显著丰富，但在EAs中完全缺失，这表明很可能存在人群特有的AD变异。我们建议利用我们和AD遗传学协会收集的大量临床和遗传资源来确定AKAP9、ABCA7和先前发现的与AD相关的基因的功能变异，这些基因直接导致AA的AD风险。为了实现这一目标，我们将对500名AA AD先证者和500名AA年龄匹配的认知正常对照组的这些基因的编码和调节区进行重新测序。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。潜在重要的功能变异将在发现AA队列和包含1000个病例和2000个对照的复制AA队列中进行关联测试。我们将尝试通过使用公开的数据评估排名最靠前的变体来确定在AA中发现的变体是否也适用于EA，从而尝试在EA中推广这些发现 在EAS中很重要。将在AA和EA病例和对照的脑组织中进行基因表达和RNA-Seq实验，以确定可能调节替代亚型转录的变异。ABCA7和AKAP9中最有希望的变体将被引入神经细胞，以评估它们对APP、tau和其他重要AD标记物表达和处理的影响。最后，我们将通过在AD患者和对照组的神经病理证实的脑标本中证明这些基因的表达改变来证实这些基因的重要性。

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.