Causality of atrial fibrillation and left atrial traits: Genetic and epigenetic perspectives

Background Atrial fibrillation (AF) is associated with left atrial (LA) abnormalities, yet the causality between them are not well defined. Objective This study aims to investigate the genetic correlations and bidirectional causality between AF and LA traits. Methods We utilized Genome-Wide Association Study (GWAS) data from FinnGen and other cohorts. Linkage disequilibrium score regression (LDSC) was applied for estimates of genetic correlations, and Mendelian Randomization (MR) analysis was conducted for causality analysis. Results LDSC revealed significant genetic correlations between LA traits and AF. Forward MR analyses established causal associations of AF on LA active emptying fraction (LAaEF) (β: -0.092, P=2.29E-14), LA minimum volume (LAmin) (β: 0.083, P=1.11E-11), and LA maximum volume (β: 0.063, P=5.43E-08), while no causal relationship was observed with LA passive emptying fraction (LApEF). Reverse MR indicated a causal effect of LAaEF on AF (OR: 0.736, P=0.003). Epigenetic MR identified three CpG sites for AF (cg27529934, cg13639451, and cg07191189) which showed causal relationships with LA traits. Moreover, LA traits were causally associated with heart failure (LAaEF: OR: 0.879, P=0.013; LAmin: OR: 1.119, P=0.037) and cardioembolic stroke (LAaEF: OR: 0.689, P=0.010; LApEF: OR: 0.556, P=0.002; LAmin: OR: 1.733, P=0.045). Conclusions LAaEF is bidirectionally causally linked with AF, underscoring its importance in the management of AF. Epigenetic modifications, as evidenced by specific CpG sites, may contribute to atrial remodeling in AF, offering new avenues for research into the AF pathophysiology.