Genetically Predicted Gut Microbial Taxa and Inflammatory Proteins Associated With Atrial Fibrillation: A Bidirectional Mendelian Randomization and Colocalization Study

ABSTRACT Background Observational studies have linked the gut microbiota and inflammatory proteins to atrial fibrillation (AF), but confounding, reverse causation, and instrument validity remain concerns. Methods We evaluated 473 microbial traits and 91 inflammatory proteins in relation to AF using two GWAS datasets. Sensitivity analyses included instruments selected at p < 5 × 10 −8 , MR‐RAPS, cis / trans ‐stratified protein MR, reverse MR, and FGF‐5 colocalization. Participants were predominantly of European ancestry. Results Under conventional IVW analysis, six associations were FDR‐significant in the discovery analysis and remained FDR‐significant when selectively evaluated in the second AF GWAS, with FDR correction applied across the six prioritized tests: Leptospirae (OR 0.605, 95% CI 0.457–0.800), Leptospirales (0.499, 0.371–0.673), leukemia inhibitory factor receptor (LIF‐R; 0.905, 0.869–0.943), TWEAK (0.891, 0.856–0.927), FGF‐5 (1.077, 1.051–1.103), and interleukin‐6 (0.886, 0.834–0.942). At p < 5 × 10 −8 , neither microbial trait had a harmonized instrument, whereas the protein estimates retained their directions. MR‐RAPS supported LIF‐R in both datasets, but support for the other signals varied. The prioritized proteins also differed in cis / trans genetic architecture. The FGF‐5 cis ‐only estimates were based on two harmonized instruments and were therefore preliminary, while cis ‐region colocalization provided little evidence of a shared variant (PP.H4 = 0.0045). Conclusions The conventional IVW associations varied in robustness across alternative analyses. These findings prioritize hypotheses, not established causal pathways or clinical targets. Generalizability beyond predominantly European populations remains uncertain.