Multimodal analysis disentangles the genetic and microbial associations between inflammatory bowel disease and other immune-mediated diseases across a harmonized population framework.

Immune-mediated inflammatory diseases (IMID) are chronic conditions with a well-established multifaceted association with the gastrointestinal diseases Crohn's disease (CD) and ulcerative colitis (UC), commonly known as inflammatory bowel disease (IBD). In this study, we leverage Danish nationwide pedigree and health data, genome-wide association studies, and fecal microbiota data to characterize the association between IBD and other IMIDs and disentangle genetic and environmental contributions. We show that CD and UC have distinct patterns of correlations with other IMIDs within families. By evaluating genetic and gut microbial correlations, we highlight a UC microbiota-linked correlation with multiple sclerosis and systemic lupus erythematosus despite a negative genetic correlation, suggesting a key role for environmental factors. In contrast, we find consistent genetic and microbial convergence between both IBD subtypes and rheumatoid arthritis, whereas genetic factors mainly drive the correlation with psoriasis. Thus, our findings uncover heterogeneity in shared etiological pathways across immune diseases, underscoring the need for stratified approaches to diagnosing and treating IBD.