Admixture mapping in late-onset Alzheimer’s disease

项目概要 混合人群中迟发性阿尔茨海默病（LOAD）的患病率和发病率较高， 加勒比海西班牙裔（CH）和非洲裔美国人（AA）比非西班牙裔白人。混合发生在 孤立的种群开始杂交的历史或社会事件，他们的后代是混合的， 遗传物质的创始人群，导致镶嵌染色体。混合物可以是一种有价值的 当疾病在不同地区有不同的频率时， 人群，例如LOAD。其他疾病检查（心血管疾病、青光眼、哮喘） 证明了混合映射的重要性，最近对AA的研究表明， 非洲血统的贡献。这在西班牙人中从未发生过。 在我们之前的调查中，我们在加勒比海西班牙裔中进行了一项大型全基因组关联研究： FBXL7基因中的一个新位点被发现与LOAD相关，沿着的还有以前已知的其他位点 在欧洲血统的大型GWAS中发现。这一新发现暗示了潜在的其他机制。 LOAD的病理生理学，并证明了混合人群在推进 了解疾病。初步结果表明，在我们的加勒比海西班牙裔样本中，LOAD病例 与健康对照组相比，具有更高的非洲血统，与先前在非洲裔美国人中的报告相匹配。 鉴于这些前提，我们假设，遗传位点与过量的祖先方面负荷贡献 在加勒比海西班牙裔中观察到的LOAD频率较高。这是基于这样的假设， 导致风险增加的致病变异更频繁地发生在染色体片段上（“祖先块”） 遗传自祖先人群的疾病风险更高。利用大样本的 具有广泛表型和遗传数据的个体，将进行精细定位的两层方法 首先，我们将在GWAS数据中进行混合作图，以确定具有风险特征的遗传位点， 不同祖先的负载（目标1）。其次，我们将对WES数据（目标2）进行分析，重点是 这些基因座通过在先前目标中进行的分析而优先化。最终，我们将寻求在功能上 通过研究新发现的基因位点在app加工、tau蛋白抑制中的作用， 和突触功能（目标3）。

PROJET SUMMARY Prevalence and incidence of late-onset Alzheimer’s disease (LOAD) are higher in admixed population such as Caribbean Hispanics (CH) and African-Americans (AA) than in non-Hispanic Whites. Admixture occurs when isolated populations begin interbreeding for historical or social events, and their offspring are mixtures of the genetic materials of the founding populations, resulting in mosaic chromosomes. Admixture can be a valuable source of statistical power to map disease-associated genes when the disease has different frequency across populations, such as LOAD. Investigations in other conditions (cardiovascular diseases, glaucoma, asthma) demonstrated the importance of admixture mapping and a recent study on AA showed the significant contribution of African ancestry in LOAD. This has never been performed in Hispanics. In our previous investigation, we performed a large genome-wide association study in Caribbean Hispanics: a novel locus in the FBXL7 gene was found to be associated with LOAD, along with other known-loci previously identified in large GWAS of European ancestry. This new finding implicates additional mechanisms underlying the pathophysiology of LOAD, and demonstrates the valuable asset of admixed populations in advancing the understanding of the disease. Preliminary results indicate that in our Caribbean Hispanic sample, LOAD cases have higher African ancestry as compared to healthy controls, matching previous reports in African Americans. Given these premises, we hypothesize that genetic loci with excess ancestry with respect to LOAD contribute to the observed higher frequency of LOAD in Caribbean Hispanics. This is based on the assumption that causal variants leading to increased risk occur more frequently on chromosomal segments (“ancestral blocks”) inherited from the ancestral population that has higher disease risk. Capitalizing on the large sample of individuals with extensive phenotype and genetic data, a two-layers approach of fine mapping will be carried out: first, we will conduct admixture mapping in GWAS data in order to identify genetic loci with risk profiles for LOAD that differ by ancestry (Aim 1). Secondly, we will conduct analyses in WES data (Aim 2) focusing on those loci prioritize by analyses conducted in the previous aim. Ultimately, we will seek to functionally characterize the newly discovered genetic loci by investigating their role in app processing, tau proteostasis and synaptic function (Aim 3).