Cross-trait mapping of shared susceptibility across inflammatory bowel disease and spondyloarthropathies

BACKGROUND: Inflammatory bowel diseases (IBDs) and spondyloarthropathies (SpAs) frequently co-occur, yet the subtype-specific genetic architecture and effector tissues that implement this gut-joint coupling remain poorly defined. METHODS: We integrated European-ancestry GWAS summary statistics for IBD, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis and enteropathic arthritis, covering 22.21 million variants across 1,263,767 individuals. We quantified genome-wide and local sharing (S-LDSC/LDSC, ρ-HESS), identified pleiotropic loci (MTAG, CPASSOC) in trait pairs with significant genome-wide genetic correlation, and prioritized shared loci by integrating local-correlation evidence with GWAS-PW and GCTA-COJO, mapped signals to tissues/cell types (LDSC-SEG, gsMap), prioritized effector genes (UTMOST, FUSION, SMR, immune-cell scPrediXcan), and assessed directionality using bidirectional Mendelian randomization. RESULTS: IBD showed 16.4% liability-scale SNP heritability (CD 21.5%; UC 15.2%), whereas SpA subtype heritability ranged from 2.4% (ReA) to 62.9% (AS). Genetic correlations were positive but heterogeneous, with the strongest sharing observed for EnA-related pairs. Local genetic analyses indicated structured but uneven regional sharing across subtype pairs, with the most robust local support concentrated in PsA- and EnA-related comparisons. Tissue and cell-type analyses converged mainly on immune- and barrier-related contexts, including blood, synovial fluid, spleen, lung, and lymphoid tissues, as well as T-lineage and myeloid immune compartments. Complementary gsMap projection suggested a developmentally informed gut-immune spatial scaffold rather than a uniform anatomical pattern. Pair-specific transcriptomic integration further prioritized recurrent candidate effectors across the IBD-SpA axis, while bidirectional Mendelian randomization supported a predominantly forward component from intestinal inflammatory liability to selected SpA phenotypes. CONCLUSION: These results provide a multi-layer genetic and biological framework for gut-joint comorbidity, implicating shared immune and barrier niches and supporting a gut-first component in the IBD-SpA axis.