# Genetic Predisposition to Lone Atrial Fibrillation and the Causal Effect on Cardiovascular Diseases: A Mendelian Randomization Study

## TL;DR

This study finds that people genetically predisposed to lone atrial fibrillation have a higher risk of stroke and heart failure, but not coronary artery disease or cardiac death.

## Contribution

The study identifies novel genetic loci for lone AF and demonstrates stronger causal effects on stroke and heart failure compared to common AF.

## Key findings

- Lone AF genetic predisposition increases stroke risk by over twofold.
- Lone AF is significantly associated with heart failure risk.
- No significant link was found between lone AF and coronary artery disease or cardiac death.

## 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.