Mechanistic Pathways Underlying Genetic Predisposition to Atrial Fibrillation Are Associated With Different Cardiac Phenotypes and Cardioembolic Stroke Risk

PMCID: PMC12173164

PMID: 40526779

DOI: 10.1161/CIRCGEN.124.004932

Journal: Circulation. Genomic and precision medicine

Publication Date: 2025-6-17

Authors: Gajendragadkar PR, Von Ende A, Murgia F, Offer A, Camm CF, et al.

Key Points

• Distinct genetic pathways for AF have differential effects on cardiac phenotypes and stroke risk
• Muscle pathway genetic variants associated with 5.58 ms longer PR interval (95% CI, 2.59 to 8.58; P=3×10−4)
• Genetic heterogeneity in AF may inform more targeted risk stratification and potential personalized therapeutic approaches

Summary

This genome-wide association study investigated the heterogeneous genetic mechanisms underlying atrial fibrillation (AF) by examining three distinct biological pathways: muscle function, cardiac development, and ion channels. By analyzing large-scale datasets including UK Biobank, the researchers demonstrated that these genetic pathways have markedly different effects on cardiac intermediate phenotypes and stroke risk, revealing the complex etiology of AF.

The study revealed nuanced differences across genetic pathways, with the muscle pathway associated with longer PR intervals, lower left atrial emptying fraction, and higher N-terminal pro-B-type natriuretic peptide levels. Notably, the ion-channel pathway was linked to a lower risk of cardioembolic stroke compared to other pathways. These findings suggest that genetic predisposition to AF is not uniform, but comprises distinct mechanistic routes with varying impacts on cardiac structure, electrical conduction, and clinical outcomes.