Shared Genetics Implicate Gut Microbiota and Immunity in Anterior Uveitis and Inflammatory Bowel Disease.

PURPOSE: Anterior uveitis (AU) is a common extraintestinal manifestation of inflammatory bowel disease (IBD). This study investigates the shared genetic architecture and pleiotropic loci between AU and IBD.

METHODS

Using large-scale GWAS data from European-ancestry cohorts, we performed LD score regression to assess genetic correlations, two-sample Mendelian randomization for causal inference, and PLACO analysis to identify pleiotropic loci. Multi-trait colocalization integrating 412 gut microbiome features was conducted using HyPrColoc. Functional annotation employed FUMA and ANNOVAR, gene-based analysis used MAGMA, and drug-gene interactions were explored via DrugBank.

RESULTS

AU showed significant genetic correlations with IBD (rg = 0.44, p = 2.0 × 10-4), ulcerative colitis (rg = 0.52, p = 6.0 × 10-4), and Crohn's disease (rg = 0.24, p = 0.029). Mendelian randomization supported causal effects of genetically predicted IBD and its subtypes on AU risk. We identified 62 pleiotropic risk loci, including 18 with strong colocalization evidence. Functional and pathway analyses revealed enrichment of these loci in immune and inflammatory pathways, mainly the IL-17/IL-23 axis and NOD2 signaling. Multi-trait colocalization further linked a shared AU-IBD risk locus to the gut microbial MEP pathway. Several pleiotropic genes (e.g. JAK2, STAT3) represent potential drug targets.

CONCLUSIONS

AU and IBD share pleiotropic genetic loci involved in immune regulatory pathways and gut microbiome-associated metabolic processes, revealing a potential molecular basis for their comorbidity and highlighting actionable therapeutic targets.