Multiomics Insights Into the Role of Spondin‐1 in the Pathogenesis and Prognosis of Atrial Fibrillation

Background Atrial fibrillation (AF) is characterized by progressive structural remodeling, yet molecular drivers remain incompletely understood. This study aimed to identify novel protein targets for AF using an integrative multiomics approach. Methods We performed a multilayered genetic screen combining Mendelian randomization and colocalization analyses of plasma protein (protein quantitative trait loci) and atrial expression quantitative trait loci with AF genome‐wide association studies. SPON1 (spondin‐1) was identified as a priority candidate and further characterized using single‐nucleus RNA sequencing, spatial transcriptomics, and experimental validation. Clinical relevance was evaluated in the UK Biobank cohort by assessing associations with incident AF, cardiac magnetic resonance phenotypes, and long‐term prognosis. Results The genetic screen identified SPON1 as a potential target for AF, supported by colocalization evidence across the plasma proteome (posterior probability of hypothesis 4=0.87) and atrial transcriptome (posterior probability of hypothesis 4=0.86). Single‐cell and spatial transcriptomics revealed that SPON1 expression was specific to fibroblasts and enriched in extracellular matrix pathways. In the UK Biobank cohort (N=39 372), elevated plasma SPON1 levels were independently associated with an increased risk of incident AF (hazard ratio [HR], 1.17; P <0.001). Furthermore, high SPON1 levels were associated with increased left atrial volumes ( P <0.05) and stratified the risk of heart failure and death (HR, 1.51; P <0.001) in patients with established AF. Experimental validation showed that recombinant SPON1 can induce a profibrotic phenotype in fibroblasts. Conclusions In conclusion, this integrative study identifies SPON1 as a candidate with potential causal and prognostic relevance for AF. These findings suggest that targeting this protein may offer a strategy for modifying the structural substrate of AF.