What question did this study set out to answer?

This research aims to explore the genetic and biological links between inflammatory bowel diseases and spondyloarthropathies.

June 15, 2026Journal of Translational Medicine0 citationsOpen Access

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

LWL Wang FLFeng Li YWYì Wáng

Key Points

This research aims to explore the genetic and biological links between inflammatory bowel diseases and spondyloarthropathies.
Integrated GWAS summary statistics for multiple traits covering over 22 million variants across 1.26 million individuals.
Conducted local and genome-wide genetic correlation analyses, identifying pleiotropic loci and prioritizing effector genes.
Mapped genetic signals to specific tissues and immune cell types, using bidirectional Mendelian randomization to assess directionality.
IBD shows 16.4% liability-scale SNP heritability (Crohn's disease 21.5%; ulcerative colitis 15.2%), while SpA heritability ranges from 2.4% to 62.9%.
High genetic correlation between certain IBD and SpA subtype pairs, especially for enteropathic arthritis-related conditions.
Findings indicate a gut-first influence of intestinal inflammation on selected SpA phenotypes, identified through bidirectional Mendelian randomization.

Abstract

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.

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