Genomic, Epigenomic, and Transcriptomic Mechanisms of Contributing to Alzheimer's Disease Risk in Diverse Ancestral Populations

不同祖先人群中阿尔茨海默病风险的基因组、表观基因组和转录组机制

• 批准号: 10301691
• 负责人: William S Bush
• 金额: $ 229.02万
• 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: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301691
• 关键词: Address; African American; Alleles; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease risk; Architecture; Bioinformatics; Biological; Biology; Caribbean region; Cognitive; Collection; Communities; Complement; Complex; DNA; DNA Methylation; Data; Data Set; Dementia; Development; Disease; Elderly; Epigenetic Process; Equilibrium; Ethnic group; Follow-Up Studies; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genetic study; Genomic approach; Genomics; Genotype; Genotype-Tissue Expression Project; High-Throughput RNA Sequencing; Hispanic Americans; Hispanics; Individual; Methods; Methylation; Modeling; Molecular; Not Hispanic or Latino; Pathway interactions; Peripheral Blood Mononuclear Cell; Peru; Peruvian; Population; Population Heterogeneity; Process; Puerto Rico; Quantitative Trait Loci; RNA; RNA Splicing; Race; Regulation; Research; Resources; Role; Sampling; Site; Statistical Methods; Susceptibility Gene; Tissues; United States; Variant; Whole Blood; aged; base; case control; caucasian American; cell type; cohort; disorder control; disorder risk; epigenetic variation; epigenomics; ethnic diversity; functional genomics; genome sequencing; genome wide association study; genome wide methylation; genome-wide; genomic data; genomic locus; multi-ethnic; multiple omics; response; risk variant; single-cell RNA sequencing; trait; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY Alzheimer disease (AD) is the leading cause of dementia in the elderly in the United States and occurs in all ethnic and racial groups. Although >20 susceptibility loci have been associated with AD, much of the genetic influence on AD remains unknown. This is particularly true for diverse ethnic populations such as Hispanics (HI) and African Americans (AA) that are underrepresented in most genetic studies compared to non-Hispanic Whites (NHW). Though emerging studies have begun to unravel some of the ancestry associated genetic risk of AD, understanding the role of DNA variation is only one critical step in understanding the complex underlying biology variants do not always provide direct information on the genes and mechanisms influenced. To expand the context of ongoing large-scale genomic genotyping and whole genome sequencing efforts to individuals of diverse ancestries, here we propose a transcriptomic, epigenomic, and genomic association study of NHW, AA, and HI from Puerto Rico (PR) and Peru (PER) addressing diverse admixed populations. Completion of this project will provide powerful functional genomic resources that could be applied to large existing and emerging AD datasets to better understand the biological impact of genetic variation on AD risk. Specifically, we will 1) generate whole-blood RNAseq, single-cell RNAseq, and DNA methylation datasets on existing collections of NHW, AA, PR, and PER AD cases and elderly cognitively normal controls; 2) identify transcriptomic and methylation differences including gene expression, alternative splicing, allele specific expression, and site and regional methylation differences between NHW, AA, and HI cases and controls that may drive disease risk differences between the ancestries; 3) combine these data with available DNA genotyping/whole genome sequencing data to identify population and disease-specific expression/methylation QTLs; 4) generate the first multiethnic imputation panel of expression/methylation QTL effects for estimating gene expression traits in diverse (NWH, AA, HI) AD datasets; and 5) apply these panels to a broader set of thousands of multi-ethnic genotyped samples. The multi-omics approach outlined here will provide much needed functional context to the ongoing DNA variant discovery efforts in these populations while addressing the important problem of disparities in AD research. These studies will broaden the spectrum of AD risk to gene expression and methylation and expand existing genomic efforts to a broader AD community.

项目摘要 阿尔茨海默氏病（AD）是美国老年人痴呆的主要原因，并发生在所有人中 种族和种族群体。尽管> 20个易感基因座与AD相关，但大部分遗传 对广告的影响仍然未知。对于诸如西班牙裔（HI）等多样化的民族人口尤其如此 与非西班牙裔白人相比，在大多数遗传研究中代表不足的非裔美国人（AA） （NHW）。尽管新兴研究已开始揭示一些与AD相关的遗传风险，但 了解DNA变异的作用只是理解复杂基础生物学的一个关键步骤 变体并不总是提供有关影响基因和机制的直接信息。 扩大正在进行的大规模基因组基因组和整个基因组测序工作的背景 各种祖先的个体，我们在这里提出了转录组，表观基因组和基因组协会研究 来自波多黎各（PR）和秘鲁（per）的NHW，AA和HI，以解决各种混合人群的态度。完成 该项目将提供强大的功能基因组资源，可以应用于大型现有和 新兴的AD数据集可以更好地了解遗传变异对AD风险的生物学影响。具体来说，我们 会在现有集合上生成全血RNASEQ，单细胞RNASEQ和DNA甲基化数据集 NHW，AA，PR和AD病例以及老年人认知正常对照； 2）识别转录组和 甲基化差异，包括基因表达，替代剪接，特异性表达和位点以及 NHW，AA和HI病例和控制可能驱动疾病风险的区域甲基化差异 祖先之间的差异； 3）将这些数据与可用的DNA基因分型/整个基因组相结合 测序数据以识别人群和疾病特异性表达/甲基化QTL； 4）生成第一个 多民族插补表达/甲基化QTL效应，用于估计基因表达性状 多样（NWH，AA，HI）广告数据集； 5）将这些面板应用于更广泛的多种族 基因分型样品。 此处概述的多词方法将为正在进行的DNA提供急需的功能环境 这些人群中的变体发现工作，同时解决广告中差异的重要问题 研究。这些研究将扩大基因表达和甲基化的AD风险范围，并扩展 现有的基因组努力为更广泛的广告社区。

项目成果

Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer's Disease Cohorts of Diverse Genetic Ancestries.

Tau 和淀粉样蛋白血浆生物标志物在不同遗传祖先的阿尔茨海默病队列中的普遍性。

• DOI: 10.1101/2024.04.10.24305617
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Griswold,AnthonyJ;Rajabli,Farid;Gu,Tianjie;Arvizu,Jamie;Golightly,CharlesG;Whitehead,PatriceL;Hamilton-Nelson,KaraL;Adams,LarryD;Sanchez,JoseJavier;Mena,PedroR;Starks,TakiyahD;Illanes-Manrique,Maryenela;Silva,Concepcion;B
• 通讯作者: B