Unraveling the Causal Association Between microRNAs and Ulcerative Colitis: A Multi-Stage Mendelian Randomization Study with External Validation

Background Circulating microRNAs (miRNAs) are frequently dysregulated in ulcerative colitis (UC), yet whether these alterations represent causes or consequences of the disease remains unclear. This study aimed to systematically investigate the causal effect of plasma miRNAs on UC risk using a comprehensive multi-stage Mendelian randomization (MR) framework. Methods We employed a two-sample MR design utilizing genetic instruments for miRNAs derived from independent cis- and trans-eQTL datasets (Nikpay et al. and Framingham Heart Study). Outcome summary statistics were obtained from the FinnGen (n = 499,380) and EBI GWAS Catalog (n = 458,440) cohorts. Analyses included inverse variance weighted estimation, rigorous sensitivity checks, Bayesian colocalization to assess pleiotropy, and reverse MR. Findings were further biologically interpreted through target gene functional enrichment and triangulated with external transcriptomic validation (GSE122618). Results The miR-130b family (miR-130b-3p and miR-130b-5p) demonstrated consistent protective effects against UC across discovery and validation phases (e.g., miR-130b-5p: OR = 0.91–0.92, P < 0.05). Conversely, miR-101-3p, miR-1908-5p, miR-27a-3p, and let-7a-5p were identified as significant risk factors. Reverse MR analyses provided no robust evidence that UC liability influences these miRNA levels. Bayesian colocalization strongly supported shared causal variants for miR-27a-3p (PP.H4 = 0.61) and miR-1908-5p. Functional enrichment linked miR-130b targets to focal adhesion and MAPK/Wnt signaling pathways critical for mucosal homeostasis. Conclusion This study provides compelling genetic evidence that specific circulating miRNAs causally influence UC susceptibility. The identification of protective (miR-130b family) and risk-increasing miRNAs advances our understanding of UC pathogenesis, highlighting these molecules as promising biomarkers and potential therapeutic targets.