Gene-gene interactions between a LMNA variant and common polymorphisms drive early-onset atrial fibrillation.

Atrial fibrillation (AF), the most common sustained arrhythmia, has a complex genetic basis; however, the molecular mechanisms linking rare and common variants remain poorly understood. Polygenic risk score (PRS) analysis in the UK Biobank and All of Us cohorts reveals that carriers of protein-altering LMNA variants (PAVs) have a significantly higher risk of incident AF than predicted by PRS alone, supporting an additive effect of common polymorphisms and LMNA variants. Induced pluripotent stem cell derived atrial cardiomyocytes (iPSC-aCMs) from individuals carrying the pathogenic missense variant p.S143P in LMNA exhibit widespread disruption of chromatin architecture and perturbation of atrial gene regulatory networks, particularly at loci harboring AF-associated variants and transcription factors essential for atrial rhythm control and contractility. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenetic editing validates the function of several AF-associated regulatory elements and their downstream targets. Notably, reduced accessibility at an intronic SCN10A enhancer harboring the AF-associated SNP rs6801957 is associated with reduced sodium current in p.S143P iPSC-aCMs. These findings are reproduced in iPSC-aCMs derived from an additional individual carrying a distinct pathogenic LMNA variant, supporting a broader mechanism in which rare LMNA variants and common polymorphisms converge on shared regulatory networks to influence AF susceptibility and highlighting the value of integrating both in arrhythmia risk assessment.