Discrete mechanistic pathways underlying genetic predisposition to atrial fibrillation are associated with different intermediate cardiac phenotypes and risk of cardioembolic stroke

Background Genome-wide association studies (GWAS) have clustered candidate genes associated with atrial fibrillation (AF) into biological pathways reflecting different pathophysiological mechanisms. We investigated whether these pathways associate with distinct intermediate phenotypes and confer differing risks of cardioembolic stroke. Methods Three distinct subsets of AF-associated genetic variants, each representing a different mechanistic pathway, i.e., the cardiac muscle function and integrity pathway (15 variants), the cardiac developmental pathway (25 variants), and the cardiac ion channels pathway (12 variants), were identified from a previous AF GWAS. Using genetic epidemiological methods and large-scale datasets such as UK Biobank, deCODE, and GIGASTROKE, we investigated the associations of these pathways with AF-related cardiac intermediate phenotypes, which included ECG parameters (~16,500 ECGs), left atrial and ventricular size and function (~36,000 cardiac MRI scans), and relevant plasma biomarkers (NT-proBNP, ~70,000 samples; high-sensitivity troponin I and T, ~87,000 samples), as well as with subtypes of ischaemic stroke (~11,000 cases). Results Genetic variants representing distinct AF-related mechanistic pathways had significantly different effects on several AF-related phenotypes. In particular, the muscle pathway was associated with a longer PR interval (P for heterogeneity between pathways [Phet] = 1 × 10-10), lower LA emptying fraction (Phet = 5 × 10-5), and higher NT-proBNP (Phet = 2 × 10-3) per log odds higher risk of AF compared to the developmental and ion channel pathways. By contrast, the ion channel pathway was associated with a lower risk of cardioembolic stroke (Phet = 0.04 in European, and 7 × 10-3 in multi-ancestry populations) compared to the other pathways. Conclusions Genetic variants representing specific mechanistic pathways for AF are associated with distinct intermediate cardiac phenotypes and a different risk of cardioembolic stroke. These findings provide a better understanding of the aetiological heterogeneity underlying the development of AF and its downstream impact on disease and may offer a route to more targeted treatment strategies.