Gene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial Fibrillation

Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF.

These electrophysiological defects are rescued by CRISPR-mediated activation of the SCN5A promoter and enhancer providing the first molecular evidence of epistatic gene-gene interactions driving arrhythmia risk and mechanistically linking atrial myopathy and AF. At the population level, we demonstrate carriers of LMNA proteinaltering variants with a high polygenic risk score are at two-fold increased risk of earlyonset AF, highlighting the need to integrate rare and common variants for more accurate AF risk assessment.