Abstract
The QT interval, a marker of ventricular repolarization, is a heritable, independent predictor of risk for ventricular arrhythmias and sudden cardiac death (SCD). Previous genome-wide association studies (GWAS) of the QT interval have highlighted pathways regulating cardiac ion channels, calcium signaling and myocyte internal structure. However, a large proportion of the heritability remains unexplained, suggesting additional mechanisms remain undiscovered. To identify new candidate genes and pathways relevant to ventricular repolarization to elucidate novel mechanisms underlying arrhythmogenesis. We performed the largest trans-ancestry QT GWAS meta-analysis to date, using 35 studies imputed with 1000G / HRC reference panels, comprising a total sample of 252,730 individuals (84% European, 7.7% Hispanic and 6.7% African ancestry/ethnicity). Candidate gene prioritisation and gene-set enrichment analyses were performed using DEPICT. We identified 176 independent loci (114 novel) associated with QT. SNP-based heritability in European ancestry UK-Biobank participants was 29.3%. The variance explained by lead and conditionally independent variants was 14.6%. Across all loci, the top 30 gene-ontology terms highlighted by DEPICT included processes involved in either muscle cell differentiation, tissue development, insulin receptor signaling or regulation of gene expression. At one locus (CD36), the association was driven by studies of African ancestry only. This gene encodes an immune-metabolic receptor necessary for appropriate myocardial substrate utilisation. Another novel locus (FAM9B) was identified in male-stratified X-chromosome analyses. Other candidate genes highlighted include cardiac Z-disk proteins (C10orf71), enzymes with cardioprotective roles in oxidative stress (PON2), cardiomyocyte glucose transporters (GLUT4) and regulators of cell morphology and cytoskeleton organization (BRWD1). Our analyses highlight novel genes and pathways associated with the QT interval that may expose new mechanisms, which contribute to arrhythmogenesis and SCD and could serve as new therapeutic targets.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call