Discovery and interrogation of genetic regulatory variation impacting Atrial Fibrillation risk

影响心房颤动风险的基因调控变异的发现和询问

基本信息

批准号：
10593080
负责人：
Xin He
金额：
$ 80.31万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593080
关键词：
ATAC-seq Address Adult Affect Alleles Arrhythmia Atrial Fibrillation Biological Biological Assay Cardiac Cardiac Myocytes Cell physiology Cells Cellular Structures Chromatin Chromosomes Complex DNA Data Data Set Disease Electrophysiology (science)Enhancers Etiology Functional disorder Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Variation Genomics Goals Heart Heart Atrium Human In Vitro Individual Link Maps Modeling Molecular Nucleic Acid Regulatory Sequences Pathway interactions Physiology Pilot Projects Principal Investigator Procedures Regulatory Element Reporter Resolution Risk Signal Transduction System Techniques Tissues Translating Untranslated RNA Variant candidate identification causal variant cell type chromosome conformation capture deep learning disorder risk economic cost experimental study gene discovery gene regulatory network genetic association genetic variant genome wide association study genomic data improved insight multimodality novel promoter risk variant socioeconomics trait transcription factor transgene expression

项目摘要

Abstract The overall goal of this multi-principal investigator proposal is to facilitate the transition from implication of genetic variants identified in extensive genome wide association studies (GWAS) of Atrial Fibrillation (AF) to the molecular mechanisms underlying AF risk. We hypothesize that a novel genomic and analytic pipeline interrogating regulatory function of genetic variation will identify candidate causative variants and their target genes, enabling the transition from simple associations to causative mechanisms for the arrhythmia. In preliminary studies, we have applied novel single cell approaches to generate cell-type-resolved high-resolution chromosome accessibility maps and taken advantage of coordinated genomic signals to link AF risk variants to candidate causative AF genes. The results describe a highly interconnected gene regulatory network for cardiac atrial gene expression. In our first aim we propose to generate multi-modal single-cell genomics data to provide higher-resolution annotation of variant effects. We will improve our computational procedure to better leverage these datasets for AF variant and gene discovery. In our second aim, we will interrogate the interconnected gene regulatory network in molecular enhancer assays and genomic chromatin conformation capture experiments, to directly examine the impact of nominated genetic variants and their physical association with candidate target genes. In our third aim, we will examine the functionality of high confidence variant SNPs in depth, including their impact on gene regulation in cis, their impact on human cardiomyocyte electrophysiology, and their impact on cardiomyocyte gene expression and chromatin status in trans. We have established a tractable strategy that will help enable the transition from AF risk variants to molecular mechanisms. We anticipate that our approach will help translate the promise of AF genetics into meaningful biological insights for AF and establish a paradigm for the molecular understanding of genetic association studies in any system.

抽象的这个多项式调查员建议的总体目标是促进含义的过渡在广泛的基因组广泛关联研究（GWAS）中鉴定出房颤（AF）与 AF风险的基础分子机制。我们假设一种新型的基因组和分析管道审问遗传变异的调节功能将识别候选病因及其目标基因，从而实现了从简单关联到心律不齐的致病机制的过渡。在初步研究，我们采用了新型的单细胞方法来产生细胞类型的高分辨率染色体可访问性图并利用协调的基因组信号将AF风险变体连接到候选病原体AF基因。结果描述了心脏高度相互联系的基因调节网络心房基因表达。在我们的第一个目标中，我们建议生成多模式的单细胞基因组学数据以提供变体效应的高分辨率注释。我们将改进计算程序以更好地杠杆作用这些用于AF变体和基因发现的数据集。在我们的第二个目标中，我们将询问互连的分子增强子测定和基因组染色质构象的基因调节网络捕获实验，直接检查指定遗传变异的影响及其与物理的联系候选靶基因。在我们的第三个目标中，我们将研究高置信度变体SNP的功能深度，包括它们对CI中基因调节的影响，它们对人心肌细胞生理学的影响，它们对反式的心肌细胞基因表达和染色质状态的影响。我们已经建立了可处理的策略，将有助于从AF风险变体到分子机制的过渡。我们预计我们的方法将有助于将AF遗传学的承诺转化为有意义的生物学见解 AF并为任何系统中遗传关联研究的分子理解建立范式。