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

• 批准号: 10442439
• 负责人: Derek Michael Dykxhoorn
• 金额: $ 138.17万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10442439
• 关键词: ATAC-seq; Affect; African; African American; African American population; African ancestry; Alzheimer' s Disease; Alzheimer' 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 group; European; 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; Lead; Maps; Microglia; Molecular; Neurons; Not Hispanic or Latino; Oligodendroglia; Pathway interactions; Peruvian; Population; Population Heterogeneity; Race; 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; genetic architecture; genome editing; genome wide association study; genomic data; genomic locus; induced pluripotent stem cell; male; promoter; rare variant; risk variant; targeted treatment; transcriptome sequencing

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的全基因组关联研究（GWAS）在识别遗传性疾病方面非常成功， 导致这种疾病的地区，但几乎所有都发生在非西班牙裔白人（NHW）中。大多数这些 相关的遗传区域位于基因组的非编码、调节区域。这意味着要理解 这些相关基因座影响AD的风险，我们必须了解这些基因座的调控结构， 基因组在这些相关区域。我们小组和其他人最近的努力试图了解 在不同的混合人群中，如非洲裔美国人（AA）和西班牙裔美国人（HI），AD的遗传基础。 这些研究表明，不同的民族和种族群体具有不同的遗传结构， 导致不同遗传易感性。然而，虽然像Encode和Gtex这样的研究已经绘制了一些 人类基因组的调控结构，他们缺乏不同人群的信息，因为这些调控 映射研究也几乎完全是在NHW中，而不一定是在实际的细胞类型中， 阿尔茨海默病（AD）的发病率。该提案将使用多种调查途径来绘制监管 非洲人和美洲印第安人基因组的结构，它们与欧洲人一起， 这些组分有助于混合的AA和HI基因组。一旦我们绘制了这个架构， 将用它来了解与罕见变异和相关非编码基因相关的疾病机制， 在AA和HI关联研究中鉴定的基因座。为了实现这一目标，我们将使用诱导性多能干细胞 从AA和HI（秘鲁）AD病例中，选择最大化非洲或美洲印第安人全球血统，以及 AA和HI患者的脑组织。与我们的合作者金福来博士在凯斯西储 大学，最先进的Hi-C技术将用于绘制两个分化的iPSC系中的相互作用 （神经元、少突胶质细胞、星形胶质细胞和小胶质细胞）以及冷冻脑组织。我们还将使用单 用细胞核RNAseq和单核ATACseq评估脑，用批量ATAC和RNAseq评估iPSC系。所有 然后，基因组数据将与欧洲基因组（NHW）的支持性现有数据一起沿着， 创建非洲和美洲印第安人的监管地图。然后，我们将从 外部AA和HI GWAS和罕见变异研究，并将它们“放置”在我们的监管机构中， 景观，以确定相互作用的基因和亚区的单倍型影响的风险，为AD在这些 人口。接下来，我们将使用CRISPRa和CRISPRi技术来验证这些相互作用。最后我们将 将所有这些数据与现有数据相结合，以帮助确定用于治疗干预的高质量遗传靶点 对于AD。