Alzheimer Disease Genetic Architecture in African Americans

描述（由申请人提供）：通过定位克隆、靶向基因分析和全基因组关联研究鉴定的基因解释了阿尔茨海默病（AD）的部分遗传成分。除了少数明显的例外，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。我们建议将我们的努力，以了解非裔美国人（AAs），一组痴呆症的发病率很高，但与欧洲裔美国人（EAs）AD的遗传结构不同的AD遗传风险因素。最值得注意的是，在AA中，ABCA 7的常见变体对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AKAP 9突变，它们在AA AD病例中显著富集，但在EA中完全缺失，这表明可能存在人群特异性AD致病变体。我们建议使用我们和AD遗传学联盟收集的广泛的临床和遗传资源来鉴定AKAP 9，ABCA 7和先前鉴定的AD相关基因中的功能变体，这些基因直接导致AA中的AD风险。为了实现这一目标，我们将在500个AA AD先证者和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进行重新测序。将使用生物信息学工具评估数据，以确定可能直接影响AD发病机制的功能变体。将在发现AA队列和包含1000例病例和2000例对照的复制AA队列中检测潜在重要功能变体的相关性。我们将尝试通过使用临床可用数据评估排名靠前的变体来概括EA中的这些发现，以确定在AA中鉴定的变体是否也 重要的是在EAs。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，以鉴定可能调节替代亚型转录的变体。ABCA 7和AKAP 9中最有希望的变体将被引入神经元细胞中，以评估它们对APP、tau和其他重要AD标志物的表达和加工的影响。最后，我们将证实这些基因的重要性，通过展示改变的表达在神经病理学证实的大脑标本AD病例和对照。

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.