Genetic Epidemiology of Early-Onset Alzheimers disease in Caribbean Hispanics and non-Hispanic Whites

项目摘要 为了进一步理清阿尔茨海默病(AD)的分子机制，并促进 绘制治疗靶点，我们提出了一个极端的表型设计：全基因组测序 早发性阿尔茨海默病(EoAD)在一大组多病、表型良好的加勒比海拉美裔人群中的研究 (CH)和非西班牙裔白人(NHW)家庭。极端表型设计(例如，早期发病年龄--Aao，FAST 与进展缓慢的人、非常高的与非常低的生物标志物水平等)通过创建更多 同质性和遗传负载的人群，并有可能揭示遗传风险因素和 在更多的异类数据集中难以识别的机制。这对于澄清AD是至关重要的 病因学和开发更有效的治疗靶点。 AD的早期研究集中在Eoad上，并确定了有限数量的高渗透性风险变体： APP、PSEN1和PSEN2.这些基因增加了淀粉样多肽的生成和/或聚集， 这一观察是当前治疗策略的基础。然而，这些已知的突变所占比例较小 Eoad的遗传基础的一半还多。许多Eoad家族并不携带已知的突变，在 已知的突变携带者AAO通常具有很高的变异性。这种无法解释的遗传成分导致Eoad 代表了我们对AD病因学理解上的一个严重差距--这一差距没有被正在进行的AD测序所填补 研究主要集中在更异质性的迟发性阿尔茨海默病(负荷)。此外，这一点 提案既包括西班牙裔白人样本，也包括非西班牙裔白人样本。少数族裔人口的加入使得 美国将检查研究不足但快速增长的人群中的Eoad风险，并绘制符合以下条件的AD风险基因 这是这一民族独有的，使人们进一步了解这种疾病的病因机制。 为了实现这些目标，我们提出了以下目标：(SA1)识别新的遗传风险因素 用于全基因组测序和靶向测序。我们将在87个多路Eoad家庭中执行WGS， 其次是基于分离和功能的生物信息学注释和优先排序。最高优先级 基因/区域将在家族中得到验证，然后将成为一组定制测序的目标 加载单例以最大限度地识别变体。(SA2)由SA1产生的假定功能基因座将是 使用定制基因分型阵列在独立的Eoad样本中进行验证，并(SA3)进行评估 使用ADSP、ADGC和WHICAP等现有负载资源对迟发性AD的概括性 数据集。最后(4)，最有趣的变异将接受快速的生物筛选程序，以 确定它们的分子效应。

Project Summary To further disentangle the molecular mechanisms underlying Alzheimer's disease (AD) and to foster the mapping of therapeutic targets, we propose an extreme phenotype design: a whole-genome sequencing (WGS) study of early-onset AD (EOAD) in a large set of multiply affected, well-phenotyped Caribbean Hispanic (CH) and non-Hispanic White (NHW) families. Extreme phenotype designs (e.g., early age-at-onset--AAO, fast vs. slow progressors, very high vs. very low biomarker levels, etc) increase statistical power by creating more homogeneous and genetically loaded populations, and have the potential to reveal genetic risk factors and mechanisms that are difficult to identify in more heterogeneous datasets. This is critical for clarifying AD etiology and developing more effective therapeutic targets. Early studies in AD focused on EOAD and identified a limited number of highly penetrant risk variants: APP, PSEN1, and PSEN2. These genes increase the generation and/or aggregation of the amyloid ß peptide, an observation that underlies current therapeutic strategies. However, these known mutations account for less than half of the genetic basis of EOAD. Many of the EOAD families do not carry known mutations, and among known mutation carriers AAO is often highly variable. This unexplained genetic component to EOAD represents a critical gap in our understanding of AD etiology—a gap not filled by the ongoing AD sequencing studies, which largely focus on the more heterogeneous late-onset form of AD (LOAD). Additionally, this proposal includes both Hispanic and non-Hispanic white samples. The inclusion of minority populations allows us to examine EOAD risk in an understudied but fast-growing population and to map AD risk loci that are unique to this ethnic group, giving further insight into the etiologic mechanisms underlying the disease. To accomplish these goals, we propose the following Aims: (SA1) Identification of novel genetic risk factors for EOAD by whole genome and targeted sequencing. We will perform WGS in 87 multiplex EOAD families, followed by bioinformatics annotation and prioritization based on segregation and function. Highest priority genes/regions will be validated in the family and then will become targets for custom sequencing in a set of EOAD singletons to maximize variant identification. (SA2) Putative functional loci resulting from SA1 will be validated in independent EOAD samples using custom genotyping arrays and (SA3) evaluated for generalizability to late-onset AD using existing LOAD resources such as the ADSP, ADGC, and WHICAP datasets. Finally (4), the most interesting variants will be subject to rapid, biological screening procedures to determine their molecular effects.