Introduction
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is part of a broader spectrum of immune-mediated inflammatory diseases (IMIDs). Clinical and epidemiological studies indicate a higher prevalence of IMIDs among patients with IBD and their first-degree relatives, with a significant proportion of patients with IBD also diagnosed with conditions such as asthma, psoriasis, and rheumatoid arthritis1,2. These patterns suggest shared genetic and/or environmental risk factors. The clinical intersections call for a multidisciplinary management strategy in which decisions account for the broader immune landscape rather than focusing on each diagnosis in isolation1,3.
Aims & Methods
This study aimed to characterize the relationship between IBD and other IMIDs and disentangle genetic and environmental contributions. This was done by analyzing the tetrachoric correlation4 between disease codes registered for 107,651 full sibling pairs born between 1910 and 2010 in the Danish nationwide health registries. We then estimated SNP-based correlations based on summary statistics from genome-wide association studies of each disease using LDSC5. Lastly, we downloaded and reanalyzed all V3-V4 16S rDNA fecal microbiota samples available from NCBI6 in a unified bioinformatical pipeline. We used this data to generate microbiota disease profiles and estimate their correlations across IBD and IMIDs.
Results
We show that CD and UC have distinct patterns of correlations with other IMIDs. Asthma and celiac disease were correlated with CD (asthma: ρ=0.12, 95% CI=0.10-0.13, celiac disease: ρ=0.12, 95% CI=0.08-0.17), but not UC within full siblings. Oppositely, sarcoidosis (ρ=0.16, 95% CI=0.13-0.19), multiple sclerosis (ρ=0.09, 95% CI=0.06-0.12), systemic lupus erythematosus (SLE) (ρ=0.19, 95% CI=0.13-0.25), and Sjögren’s syndrome (ρ=0.15, 95% CI=0.10-0.20) correlated with UC but not CD. The IMIDs Graves’ disease, type 1 diabetes, iridocyclitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis correlated with both CD and UC. Evaluating genetic and gut microbial correlations highlighted that UC exhibits microbiota-linked correlations with multiple sclerosis (ρ=0.11, 95% CI=0.01-0.21) and SLE (ρ=0.15, 95% CI=0.05-0.24) despite an estimated negative genetic overlap (multiple sclerosis: ρ=-0.18, 95% CI=-0.32--0.04, SLE: ρ=-0.21, 95% CI=-0.32--0.09), suggesting a key role for environmental factors, including microbial. In contrast, for both IBD subtypes rheumatoid arthritis showed consistent genetic (CD: ρ=0.12, 95% CI=0.02-0.21, UC: ρ=0.17, 95% CI=0.08-0.27) as well as microbial convergence (CD: ρ=0.30, 95% CI=0.20-0.38, UC: ρ=0.12, 95% CI=0.02-0.22), whereas the correlation with psoriasis appeared to be mainly genetically driven (CD SNP correlation: ρ=0.23, 95% CI=0.14-0.33, CD microbiota correlation: ρ=-0.13, 95% CI=-0.23--0.03, UC SNP correlation: ρ=0.25, 95% CI=0.15-0.35, UC microbiota correlation: ρ=0.06, 95% CI=-0.04-0.16).
Conclusion
These findings uncover heterogeneity in shared etiological pathways across immune diseases, underscoring the need for stratified approaches to diagnosis and therapeutic intervention in IBD. Importantly, our findings demonstrate that CD and UC—though often co-studied—harbor distinct immunogenetic and microbial associations, reinforcing the need for subtype-specific approaches in clinical management and research design. Further, the correlation between IBD and other IMIDs appears to be driven by different genetic and environmental mechanisms, which must be further explored.
References
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5. Bulik-Sullivan B, Finucane HK, Anttila V, et al. An atlas of genetic correlations across human diseases and traits. Nature Genetics 2015 47:11 2015;47:1236–1241. Available at: https://www.nature.com/articles/ng.3406 [Accessed March 14, 2025].
6. Sayers EW, Bolton EE, Brister JR, et al. Database resources of the national center for biotechnology information. Nucleic Acids Res 2022;50:D20–D26. Available at: https://pubmed.ncbi.nlm.nih.gov/34850941/ [Accessed March 14, 2025].
Disclosure
TJ reports consultancy for Ferring and Pfizer. The remaining authors have no disclosures.
