Genetic and Molecular Underpinnings of Atrial Fibrillation

Abstract

Atrial fibrillation (AF), the most common sustained arrhythmia, increases stroke and heart failure risks. Here we review genes linked to AF and mechanisms by which they alter AF risk. We highlight gene expression differences between atrial and ventricular cardiomyocytes, regulatory mechanisms responsible for these differences, and their potential contribution to AF. Understanding AF mechanisms through the lens of atrial gene regulation is crucial to improving AF treatment.

Figure 1.. aCM and vCM specific features.

a, Micrographs of the adult mouse ventricular and atrial myocardium. b, Volcano plot of pseudobulk RNA-seq analysis of human heart atlas data, comparing aCMs and vCMs. Samples with >500 aCM or vCMs were analyzed in pseudobulk using DEseq2. Genes with ∣ Log2FC ∣ > 1 and Padj.<0.05 were defined as being chamber selective. c, Ratio of atrial to ventricular gene expression in human vs mouse. Human and mouse data were plotted against each other to examine species-specific biases in chamber selectivity. The Pearson correlation coefficient (r = 0.4, p=1.78E-40) was determined for genes that were differentially expressed in both datasets. d, Venn-diagrams showing the overlap for aCM-sel. and vCM-sel. genes from the mouse and human datasets. P values, hypergeometric test.

Figure 2.. aCM- and vCM-selective expression in genes associated with AF.

a, Left, out of the 216 genes identified by GWAS studies with association to AF, 19% were selectively expressed at greater levels in aCMs compared to vCMs in either mouse or humans, or both, while only 12% of genes exhibited vCM-selectivity. Right, selective genes are broken down by species. b, Chamber selective expression was examined for GWAS genes based on functional category, and statistical differences in categorical distribution from the population was determined using the Chi-square test. P values are given in the figure. c, chamber selective expression was examined for coding variant genes based on functional category. No statistical differences were identified by chi-square test.