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Identifying Cis-Regulatory Variants, Genes, and Regulatory Networks Underlying QT Interval Variation

识别 QT 间期变异背后的顺式调控变异、基因和调控网络

基本信息

批准号：
10612015
负责人：
Ashish Kapoor
金额：
$ 52.18万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612015
关键词：
Action Potentials Adult Affect Alleles Arrhythmia Binding Biological Assay Cardiac Cardiac Myocytes Cells Chromatin Chromosome Mapping Clustered Regularly Interspaced Short Palindromic Repeats Code Communities Complex Coupling Dependence Disease Down-Regulation Electrocardiogram Electrophysiology (science)Elements Embryo Enhancers Gene Expression General Population Genes Genetic Genetic Determinism Genetic Polymorphism Genetic study Heritability Heritable Quantitative Trait Human Ion Channel Gating Knowledge Lead Left ventricular structure Linear Regressions Link Luciferases Maps Modeling Molecular Molecular Genetics Mus Muscle Cells Mutation Neonatal Penetrance Population Prevalence Proteins Quantitative Trait Loci Rattus Regulation Regulatory Element Reporter Resources Risk Short QT syndrome Signal Transduction Site Testing Tissues Untranslated RNA Up-Regulation Variant Ventricular Zebrafish base candidate identification causal variant clinically relevant differential expression disorder risk epigenomics gene discovery gene regulatory network genome wide association study in silico in vivo indexing induced pluripotent stem cell derived cardiomyocytes knowledge base member mortality risk sudden cardiac death trait transcription factor transcriptome transcriptome sequencing voltage

项目摘要

PROJECT SUMMARY/ABSTRACT Electrocardiographic QT interval, an index of ventricular repolarization, is a clinically relevant heritable quantitative trait associated with risk for cardiac arrhythmias and sudden cardiac death (SCD). Genetic studies in subjects with rare Mendelian long- and short-QT syndromes have identified rare, severe coding mutations in ~20 genes encoding voltage-gated ion channels, transporters and associated proteins that regulate cardiac action potential duration (APD) or excitation-contraction (EC) coupling. Prevalence of coding polymorphisms in these genes affecting population repolarization variability is extremely low. In contrast, genome-wide association studies (GWAS) of QT interval in the general population have identified common, noncoding variants at nearly three dozen loci, collectively explaining ~20% of the additive variance. Nearly half of these GWAS loci harbor genes known to regulate cardiac APD or EC coupling, thus serving as the likely causal genes. Nonetheless, the identities of the actual causal genes and molecular mechanisms underlying associations with the common and, largely noncoding variants at these loci, remain unknown. Moreover, a large fraction (~80%) of the additive variance remains unidentified. Leveraging information on known genes, in the proposed studies we will address these gaps in our knowledge based on the hypotheses that a) multiple common variants that impact the activities of several cis-regulatory elements (CREs) underlie a GWAS signal by collectively influencing the expression of a target gene, and b) genes underlying specific or similar diseases/traits are often functionally related, and that functionally related genes often belong to gene regulatory networks (GRNs), members of which are co-regulated. We aim to functionally characterize selected QT interval GWAS loci with a priori evidence for likely causal genes as well as extend gene discovery by assessing the impacts of perturbing the expression of known QT interval genes on their GRNs. Our specific aims are: (1) identification of functional CRE variants at selected QT interval GWAS loci by evaluating all trait-associated common variants overlapping cardiac open chromatin regions in high-throughput reporter assays in mouse cardiomyocyte HL1 cells; and to link CREs and their variants to putative target genes based on expression quantitative trait locus and chromatin contact analyses in human adult left ventricle tissue and induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs); and (2) performing CRISPR activation/interference-based expression perturbations of selected QT interval genes in neonatal rat ventricular myocytes (NRVMs), and assessing transcriptome-wide effects to identify candidate co-regulated gene sets; evaluating the co-regulated gene sets for enrichment in sub-threshold GWAS loci; overlapping co-regulated genes with QT GWAS loci to identify likely causal genes; and assessing the impact of perturbing expression of newly identified genes on cellular electrophysiology in NRVMs and hiPSC-CMs. Together, the proposed studies are expected to lead to a better understanding of the molecular mechanisms underlying QT interval variation and SCD risk, and serve as a model for functional characterization of GWAS loci of complex diseases and traits.

项目总结/文摘