GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE294nnn/GSE294948/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294948GEOGSEfalseGene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial FibrillationAtrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. 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.2026/04/10GSE294948GSM9561830GSM9561831GSM9561832GSM8931885GSM8931884GSM8931883GSM8931882GSM8931881GSM89318803428434281294948Homo sapiens