{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE294nnn/GSE294948/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294948"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Gene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial Fibrillation","description":"Atrial 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.","dates":{"publication":"2026/04/10"},"accession":"GSE294948","cross_references":{"GSM":["GSM9561830","GSM9561831","GSM9561832","GSM8931885","GSM8931884","GSM8931883","GSM8931882","GSM8931881","GSM8931880"],"GPL":["34284","34281"],"GSE":["294948"],"taxon":["Homo sapiens"]}}