Genetically Predicted Serum miRNAs as Potential Causal Drivers of Atopic Dermatitis: Evidence from Large-Scale GWAS and Clinical Validation

Background: Although dysregulated microRNAs (miRNAs) are implicated in Atopic Dermatitis (AD), their causal roles remain elusive due to potential confounding and reverse causation. We aimed to systematically identify causal miRNAs for AD and elucidate their underlying mechanisms. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) study using large-scale GWAS summary statistics for 2083 miRNAs and AD. The findings were validated using independent trans- and cis-eQTL datasets, and consistency was assessed via correlation analysis. Bayesian colocalization was applied to distinguish pleiotropy from linkage disequilibrium. Downstream targets were analyzed via GO/KEGG enrichment, and clinical relevance was verified using differential expression analysis in two independent patient cohorts (GSE162926 and GSE217232). Results: We identified six circulatory miRNAs causally associated with AD. Notably, miR-1908-5p, miR-148a-3p, miR-133a-3p were identified as a robust risk factor, while miR-125a-5p, miR-181b-5p, let-7e-5p exhibited a protective effect. Colocalization analysis revealed compelling evidence (PP.H4=0.99) for a shared causal variant (rs174561) between miR-1908-5p and AD. Reverse MR indicated no causal effect of AD on these miRNAs. Functional enrichment analyses revealed that downstream targets were predominantly enriched in the PI3K-Akt and MAPK signaling pathways, regulating biological processes critical for skin barrier integrity, wound healing, and oxidative stress response. Crucially, transcriptomic analysis in clinical cohorts corroborated the MR findings, showing significant dysregulation of the identified miRNAs in AD patients. Conclusion: This study provides robust genetic and transcriptomic evidence for the causal involvement of specific circulating miRNAs, particularly miR-1908-5p, in AD pathogenesis. These findings offer potential novel biomarkers and therapeutic targets for precision medicine in AD. Keywords: miRNAs, atopic dermatitis, Mendelian randomization, Bayesian colocalization, linkage disequilibrium