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

CD and UC have distinct patterns of familial correlations with other immune-mediated inflammatory diseases.

• The study leveraged Danish nationwide pedigree and health registry data to characterize familial disease co-occurrence patterns.
• CD and UC showed different correlation profiles with IMIDs including rheumatoid arthritis, psoriasis, multiple sclerosis, and systemic lupus erythematosus within families.
• The analysis used a harmonized population framework integrating pedigree, genomic, and microbiota data.

UC shows a microbiota-linked correlation with multiple sclerosis and systemic lupus erythematosus despite a negative genetic correlation between these conditions.

• Gut microbial correlations between UC and multiple sclerosis and between UC and systemic lupus erythematosus were identified using fecal microbiota data.
• The genetic correlation between UC and these two diseases was negative, contrasting with the positive microbial correlation.
• This discordance suggests a key role for environmental factors, particularly the gut microbiome, in driving the association between UC and these IMIDs.

Both IBD subtypes show consistent genetic and microbial convergence with rheumatoid arthritis.

• Both CD and UC demonstrated concordant genetic and gut microbial correlations with rheumatoid arthritis.
• This convergence suggests shared etiological pathways involving both genetic and environmental (microbial) factors for IBD-rheumatoid arthritis associations.
• The finding was identified through integrated analysis of genome-wide association studies and fecal microbiota data.

The correlation between IBD and psoriasis is primarily driven by genetic factors rather than environmental or microbial factors.

• Genetic correlations between IBD subtypes and psoriasis were identified using genome-wide association study data.
• Microbial correlations did not similarly explain the IBD-psoriasis association, in contrast to the IBD-rheumatoid arthritis relationship.
• This suggests genetic factors are the main driver of shared etiology between IBD and psoriasis.

The study employed a multimodal analytical framework integrating nationwide pedigree data, genome-wide association studies, and fecal microbiota data to disentangle genetic and environmental contributions to IBD-IMID associations.

• Danish nationwide pedigree and health registry data were harmonized with genomic and microbiota datasets.
• The framework allowed decomposition of familial correlations into genetic and environmental components.
• Gut microbial correlations were computed from fecal microbiota data as a proxy for shared environmental exposures.
• GWAS data were used to estimate genetic correlations between disease pairs.

The findings reveal heterogeneity in shared etiological pathways across immune-mediated diseases, with different disease pairs showing distinct combinations of genetic and microbial overlap.

• Some disease pairs (UC-MS, UC-SLE) showed discordant genetic and microbial correlations, implying environmental dominance.
• Other pairs (IBD-rheumatoid arthritis) showed concordant genetic and microbial correlations, implying joint genetic-environmental etiology.
• The IBD-psoriasis pair showed primarily genetic concordance with limited microbial contribution.
• The authors conclude this heterogeneity 'underscores the need for stratified approaches to diagnosing and treating IBD.'