Admixture mapping in late-onset Alzheimer’s disease

迟发性阿尔茨海默病的混合图谱

• 批准号: 9226309
• 负责人: Giuseppe Tosto
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226309
• 关键词: Admixture; Affect; African; African American; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Asthma; Cardiovascular Diseases; Caribbean Hispanic; Chromosomes; Clinical; Data; Dementia; Diagnosis; Disease; Disease susceptibility; Ethnic group; European; Event; Exhibits; Family Study; Family history of; Frequencies; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Materials; Genetic Risk; Genetic study; Genome; Genomic Segment; Glaucoma; Goals; Hispanics; Incidence; Individual; Inherited; Investigation; Late Onset Alzheimer Disease; Maps; Methods; Modeling; Multicenter Studies; Not Hispanic or Latino; Pathogenesis; Pathway interactions; Phenotype; Population; Prevalence; Probability; Process; Reporting; Risk; Role; Sampling; Socioeconomic Status; Source; Susceptibility Gene; Synapses; Time; Variant; admixture mapping; base; case control; cohort; disorder risk; exome sequencing; genetic profiling; genetic risk factor; genome wide association study; genome-wide; high risk; neglect; neuropsychological; next generation sequencing; novel; offspring; rare variant; risk variant; social; synaptic function; tau Proteins

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).

Projet摘要 在混合人群中，晚期阿尔茨海默氏病（负载）的患病率和发病率较高 加勒比西班牙裔（CH）和非裔美国人（AA）比非西班牙裔白人。何时发生混合 孤立的人群开始杂交历史或社会事件，他们的后代是 基础人群的遗传材料，导致镶嵌染色体。混合可能是有价值的 当该疾病在各个频率上有不同的频率时，统计能力的来源 种群，例如负载。在其他情况下进行的研究（心血管疾病，青光眼，哮喘） 证明了混合映射的重要性和对AA的最新研究表明了重要的 非洲血统在负载中的贡献。这从来没有在西班牙裔中进行。 在我们先前的调查中，我们在加勒比海西班牙裔中进行了一项大型全基因组协会研究： 发现FBXL7基因中的新基因座与负载有关 在欧洲血统的大型GWA中确定。这个新发现实现了基础的其他机制 负载的病理生理学，并证明了混合种群的宝贵资产 对疾病的理解。初步结果表明，在我们的加勒比海西班牙裔样本中 与健康对照组相比，具有更高的非洲血统，与非洲裔美国人的先前报道相匹配。 鉴于这些前提，我们假设具有载荷的遗传基因座超过祖先 观察到的加勒比西班牙裔载荷频率更高。这是基于以下假设 导致风险增加的因果变异在染色体段（“祖先块”）上更频繁地发生。 源自具有较高疾病风险的祖先人群。利用大型样本 具有广泛表型和遗传数据的个体，将携带两层绘制的方法 出局：首先，我们将在GWAS数据中进行混合映射，以识别具有风险概况的遗传基因座 通过祖先加载这种不同（AIM 1）。其次，我们将在WES数据中进行分析（AIM 2），重点关注 这些基因座通过先前目标中进行的分析来优先。最终，我们将寻求功能 通过研究其在应用程序处理中的作用，表征新发现的遗传基因座 和突触功能（AIM 3）。