Functional genomic studies in diverse populations to characterize risk loci for Alzheimer Disease

在不同人群中进行功能基因组研究，以确定阿尔茨海默病的风险位点

基本信息

批准号：
10681312
负责人：
Derek Michael Dykxhoorn
金额：
$ 138.09万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681312
关键词：
ATAC-seq Affect African African American African American population African ancestry Alzheimer&apos s Disease Alzheimer&apos s disease risk Americas Amerindian Architecture Area Astrocytes Automobile Driving Autopsy Brain CRISPR interference CRISPR-mediated transcriptional activation Candidate Disease Gene Caribbean region Cell Nucleus Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Data Databases Disease Enhancers Ethnic Population European European ancestry Female Freezing Future Gene Activation Genes Genetic Genetic Predisposition to Disease Genome Genomic Segment Genomics Genotype-Tissue Expression Project Haplotypes Hi-C Hispanic Populations Human Genome Intervention Investigation Knowledge Latino Population Maps Microglia Molecular Neurons Not Hispanic or Latino Oligodendroglia Pathway interactions Peruvian Population Population Heterogeneity Regulator Genes Resources Risk Sampling Techniques Therapeutic Intervention Universities Untranslated RNA XCL1 gene brain tissue causal variant cell type frontal lobe functional genomics gene function gene interaction genetic architecture genome editing genome wide association study genomic data genomic locus induced pluripotent stem cell male promoter racial population rare variant risk variant targeted treatment transcriptome sequencing

项目摘要

PROJECT SUMMARY Genome Wide Association Studies (GWAS) studies in AD have been very successful in identifying genetic regions contributing to the disease, but almost all have been in Non-Hispanic Whites (NHW). Most of these associated genetic regions lie in non-coding, regulatory areas of the genome. That means to understand how these associated loci influence the risk of getting AD, we must understand the regulatory architecture of the genome in these associated regions. Recent efforts from our group and others have sought to understand the genetic underpinning of AD in diverse, admixed populations such as African Americans (AA) and Hispanics (HI). These studies have shown that different ethnic and racial groups having distinct genetic architectures that can lead to differing genetic susceptibility. However, while studies like Encode and Gtex have mapped some of the regulatory architecture of the human genome, they lack information on diverse populations, as these regulatory mapping studies have also been almost exclusively in NHW, and not necessarily in the actual cell types that are affected in Alzheimer disease (AD). This proposal will use multiple avenues of investigation to map the regulatory architecture of the African and Amerindian Genomes, which, together with European, are the components that contribute to the admixed AA and HI genomes. Once we have this architecture mapped, we will use it to understand the mechanisms of disease associated with rare variants and associated non-coding loci identified in AA and HI association studies. To accomplish this, we will use inducible pluripotent stem cells from AA and HI (Peruvian) AD cases, chosen to maximize either African or Amerindian global ancestries, as well as brain tissue from AA and HI individuals. With our collaborator Dr. Fulai Jin at Case Western Reserve University, state of the art Hi-C techniques will be used to map interactions in both the differentiated iPSC lines (neurons, oligodendrocytes, astrocytes and microglia) as well as the frozen brain tissue. We will also use single nuclei RNAseq and single nuclei ATACseq to evaluate the brains, bulk ATAC and RNAseq for iPSC lines. All the genomic data will then be complied, along with supporting existing data from European genomes (NHW), to create the African and Amerindian regulatory maps. We will then take the identified associated haplotypes from the outside AA and HI GWAS and rare variant studies and “lay” them across our regulatory landscape to identify the interacting genes and subregions of the haplotypes affecting the risk for AD in these populations. Next we will use CRISPRa and CRISPRi techniques to verify these interactions. Finally, we will incorporate all this data with existing data to help identify high quality genetic targets for therapeutic intervention for AD.

项目摘要 AD的基因组广泛关联研究（GWAS）研究在鉴定遗传方面非常成功促成该疾病的地区，但几乎全部都在非西班牙裔白人（NHW）中。其中大多数相关的遗传区域在于基因组的非编码，调节区域。这意味着了解如何这些相关的地方影响获得广告的风险，我们必须了解这些相关区域中的基因组。我们小组和其他人的最新努力试图了解在潜水员中，AD的遗传基础，诸如非洲裔美国人（AA）和西班牙裔（HI）之类的混杂人群。这些研究表明，具有不同遗传体系结构的不同种族和种族群体可以导致区分遗传敏感性。但是，尽管Encode和GTEX之类的研究已绘制了一些人类基因组的监管结构，他们缺乏有关潜水员人群的信息，因为这些监管映射研究也几乎仅在NHW中，不一定在实际的细胞类型中在阿尔茨海默氏病（AD）受到影响。该提案将使用多个调查途径来映射监管非洲和美洲印第安人基因组的建筑，与欧洲一起是有助于混合AA和HI基因组的组件。一旦我们绘制了此架构，我们将使用它来了解与罕见变体和相关非编码相关的疾病机制本地化在AA和HI协会研究中。为此，我们将使用可诱导的多能干细胞从AA和HI（秘鲁）AD案件中，也选择最大化非洲或美国全球祖先作为来自AA和HI个体的脑组织。与我们的合作者Fulai Jin博士在Case Western Reserve一起大学，ART HI-C技术将用于绘制两种差异化的IPSC线路的互动（神经元，少突胶质细胞，星形胶质细胞和小胶质细胞）以及冷冻的脑组织。我们还将使用单个核RNASEQ和单核ATACSEQ用于评估IPSC线的大脑，大量ATAC和RNASEQ。全部然后，将遵守基因组数据，并支持欧洲基因组（NHW）的现有数据创建非洲和美国的监管地图。然后，我们将从外部AA和HI GWAS以及罕见的变体研究，并在我们的监管中“放置”它们景观以识别影响AD风险的单倍型的相互作用基因和子区域人群。接下来，我们将使用CRISPRA和CRISPRI技术来验证这些相互作用。最后，我们会的将所有这些数据与现有数据合并在一起，以帮助确定治疗干预的高质量遗传靶标对于广告。