Identification of candidate causalcis-regulatory variants underlying electrocardiographic QT interval GWAS loci

Abstract

AbstractIdentifying causal variants among tens or hundreds of associated variants at each locus mapped by genome-wide association studies (GWAS) of complex traits is a challenge. As vast majority of GWAS variants are noncoding, sequence variation atcis-regulatory elements affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following thiscis-regulatory hypothesis and combining it with the observation that nucleosome-free open chromatin is a universal hallmark of all types ofcis-regulatory elements, we aimed to identify candidate causal regulatory variants underlying electrocardiographic QT interval GWAS loci. At a dozen loci, selected for higher effect sizes and a better understanding of the likely causal gene, we identified and included all common variants in high linkage disequilibrium with the GWAS variants as candidate variants. Using ENCODE DNase-seq and ATAC-seq from multiple human adult cardiac left ventricle tissue samples, we generated genome-wide maps of open chromatin regions marking putative regulatory elements. QT interval associated candidate variants were filtered for overlap with cardiac left ventricle open chromatin regions to identify candidate causalcis-regulatory variants, which were further assessed for colocalizing with a known cardiac GTEx expression quantitative trait locus variant as additional evidence for their causal role. Together, these efforts have generated a comprehensive set of candidate causal variants that are expected to be enriched forcis-regulatory potential and thereby, explaining the observed genetic associations.