Abstract
Background: Lone atrial fibrillation (AF) is characterized by the absence of discernible risk factors, yet its long-term prognostic implications remain unclear. We evaluated genetic predisposition to lone AF and conducted a Mendelian randomization (MR) study to assess its causal effect on cardiovascular outcomes. Methods: A genome-wide association study (GWAS) for lone AF, along with common AF was conducted using UK Biobank data. Lone AF was defined as AF occurring without clinical risk factors. Summary-level data for cardiovascular phenotypes were obtained from publicly available GWAS datasets and the causal effects were estimated using MR. Results: We identified 36 single-nucleotide polymorphisms associated with lone AF, including two novel loci. In MR analyses, lone AF was significantly associated with an increased risk of stroke (odds ratio [OR] 2.62, 95% confidence interval [CI] 2.14-3.22) and heart failure (HF) (OR 2.55, 95% CI 2.14-3.04). The associations with coronary artery disease (CAD) (OR 0.90, 95% CI 0.73-1.10) and cardiac death (OR 1.32, 95% CI 0.99-1.77) were not significant. MR analyses of common AF also demonstrated significant associations with stroke (OR 1.86, 95% CI 1.69-2.04) and HF (OR 1.71, 95% CI 1.59-1.84), though the effect sizes were smaller compared to those of lone AF. Conclusions: Genetic predisposition to lone AF is associated with more than a twofold increase in the risk of stroke and HF. However, no clear association was observed between lone AF and CAD or cardiac death.