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：
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
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/10442439
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 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

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.

项目概要 AD 的全基因组关联研究 (GWAS) 在识别遗传方面非常成功导致该疾病的地区，但几乎所有地区都发生在非西班牙裔白人 (NHW) 中。相关的遗传区域位于基因组的非编码调控区域，这意味着了解如何进行。这些相关基因座会影响患 AD 的风险，我们必须了解该基因座的监管架构我们小组和其他人最近的努力试图了解这些相关区域的基因组。 AD 在不同的混合人群中的遗传基础，例如非裔美国人 (AA) 和西班牙裔 (HI)。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，可以然而，虽然 Encode 和 Gtex 等研究已经绘制了一些基因图谱。由于人类基因组的调控结构，他们缺乏不同人群的信息，因为这些调控绘图研究也几乎完全是在 NHW 中进行的，而不一定是在实际的细胞类型中进行的。该提案将使用多种调查途径来绘制监管图。非洲和美洲印第安人基因组的结构，它们与欧洲人一起，是一旦我们绘制了这个架构，我们就可以找到有助于混合 AA 和 HI 基因组的成分。将用它来了解与罕见变异和相关非编码相关的疾病机制为了实现这一目标，我们将使用诱导型多能干细胞。来自 AA 和 HI（秘鲁）AD 案例，选择最大化非洲或美洲印第安人的全球血统，以及来自 AA 和 HI 个体的脑组织，与我们的合作者凯斯西储大学的 Fulai Jin 博士合作。大学最先进的 Hi-C 技术将用于绘制两个差异化 iPSC 系中的相互作用图谱（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个细胞。用于评估大脑的核 RNAseq 和单核 ATACseq，用于 iPSC 系的批量 ATAC 和 RNAseq。然后将编译基因组数据以及支持欧洲基因组 (NHW) 的现有数据，以然后，我们将从中获取已识别的相关单倍型，创建非洲和美洲印第安人的监管图谱。外部 AA 和 HI GWAS 以及罕见变异研究，并将它们“放置”在我们的监管范围内景观来识别影响这些人群患 AD 风险的基因和单倍型子区域的相互作用接下来我们将使用 CRISPRa 和 CRISPRi 技术来验证这些相互作用。将所有这些数据与现有数据相结合，以帮助确定治疗干预的高质量遗传目标对于公元