Uncovering Novel Atrial Fibrillation Genetics Through Pleiotropic Overlap with Life’s Essential 8

Background/Objectives: Atrial fibrillation (AF) is a complex polygenic disorder; its genetic architecture remains challenging to fully elucidate. Methods: In this study, we leveraged the extensive genetic overlap between AF and a spectrum of cardiometabolic and behavioral factors—collectively defined by Life’s Essential 8 (LE8)—to advance our understanding of its etiology. Results: We first estimated significant genetic correlations between AF and all LE8 components (rg: −0.11 to 0.19) using LD score regression. We then applied conditional false discovery rate analysis and detected 970 pleiotropic loci associated with AF and at least one LE8 trait. Subsequent colocalization analysis identified 179 loci harboring shared causal variants between AF and one or more LE8 components, which were further refined into 137 distinct colocalized regions. Through region-based annotation and functional predictors, we finally prioritized 164 candidate genes from these colocalized loci, including 40 novel genes. These candidate genes were enriched in pathways related to heart development and regulation of cardiac contraction, and were also enriched among molecular targets of otological agents. Among all LE8 components, blood pressure demonstrated the most extensive shared genetic architecture with AF, supported by the strongest genetic correlation, highest pleiotropic enrichment, and the greatest number of colocalized loci with AF. Polygenic risk scores constructed from these colocalized loci demonstrated significant associations not only for AF but also for arrhythmia and heart failure. Conclusions: Our findings establish a genetic pleiotropy-informed framework that enhances the discovery of novel risk loci of AF and advances our understanding of the shared genetic architecture and potential biological mechanisms between AF and LE8 components.