Abstract
BACKGROUND: Genome-wide association studies 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, that is, 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 previous AF genome-wide association studies. 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 electrocardiogram parameters (≈16 500 electrocardiograms), left atrial and ventricular size and function (≈36 000 cardiac magnetic resonance imaging scans), and relevant plasma biomarkers (N-terminal pro-B-type natriuretic peptide, ≈70 000 samples; high-sensitivity troponin I and T, ≈87 000 samples), as well as with subtypes of ischemic 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 [P(het)]=1×10(-10)), lower left atrial emptying fraction (P(het)=5×10(-5)), and higher N-terminal pro-B-type natriuretic peptide (P(het)=2×10(-3)) per log-odds higher risk of AF compared with the developmental and ion-channel pathways. In contrast, the ion-channel pathway was associated with a lower risk of cardioembolic stroke (P(het)=0.04 in European, and 7×10(-)(3) in multiancestry populations) compared with 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 etiological heterogeneity underlying the development of AF and its downstream impact on disease and may offer a route to more targeted treatment strategies.