Language
English
Publication Date
6-1-2025
Journal
Circulation: Genomic and Precision Medicine
DOI
10.1161/CIRCGEN.124.005032
PMID
40421528
PMCID
PMC12173768
PubMedCentral® Posted Date
6-1-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Background: Identifying causal variants among tens or hundreds of associated variants at each locus in genome-wide association studies is challenging. As the vast majority of genome-wide association studies variants are noncoding, sequence variation at cis-regulatory elements (CREs) affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this hypothesis, combined with the observation that open chromatin is a universal hallmark of all types of CREs, we aimed to identify candidate causal cis-regulatory variants underlying QT interval genome-wide association studies loci.
Methods: Common variants in high linkage disequilibrium with genome-wide significant variants were identified using variant call format tools. Genome-wide maps of cardiac putative CREs were generated by MACS2-based peak calling in human cardiac left ventricular DNase I sequencing and Assay for Transposase-Accessible Chromatin using sequencing data sets (n=13). Variant-CRE overlap was performed using custom tracks in the Table Browser tool at the UCSC Genome Browser. Luciferase reporter-based enhancer assays for variant-centered test elements were performed in mouse HL1 cardiomyocyte cells. Reporter activities of allelic pairs were compared using the Wilcoxon rank-sum test.
Results: At a dozen genome-wide association studies loci, selected for higher effect sizes and better understanding of the likely causal genes, we identified all genome-wide significant variants (n=1401) and included all common variants (minor allele frequency >1%) in high linkage disequilibrium (r2>0.9) with them as candidate variants (n=3482). Candidate variants were filtered for overlap with cardiac left ventricular putative CREs to identify candidate causal cis-regulatory variants (n=476), which were further assessed for being a known cardiac expression quantitative trait locus variant as additional functional evidence (n=243). Functional evaluation of a subset of seven candidate variants by luciferase reporter-based enhancer assays in HL1 cells using variant-centered test elements led to the identification of 6 enhancer variants with significant allelic differences.
Conclusions: These efforts have generated a comprehensive set of candidate causal variants expected to be enriched for cis-regulatory potential and thereby, explaining the observed genetic associations.
Keywords
Genome-Wide Association Study, Humans, Animals, Mice, Linkage Disequilibrium, Electrocardiography, Polymorphism, Single Nucleotide, Myocytes, Cardiac, Enhancer Elements, Genetic, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Cell Line, QT interval, genome-wide association study, cis-regulatory variation, chromatin accessibility, expression quantitative trait locus, linkage disequilibrium, cardiomyocyte, left ventricle
Published Open-Access
yes
Recommended Citation
Kadagandla, Supraja; Gunamalai, Lavanya; Lee, Dongwon; et al., "Identification and Functional Assessment of Candidate Causal Cis-Regulatory Variants Underlying Electrocardiographic QT Interval GWAS Loci" (2025). The Brown Foundation: Institute of Molecular Medicine. 107.
https://digitalcommons.library.tmc.edu/molecular_med/107