Integrative analysis of genetic and cellular interactions connecting inflammatory bowel disease and primary biliary cholangitis.

BACKGROUND

Inflammatory bowel disease (IBD) and primary biliary cholangitis (PBC) have been reported to coexist in some patients, but the extent of this association remains to be further clarified. Clarifying their shared genetic architecture and intercellular interaction patterns may provide insight into the biological links between these two immune-mediated diseases and inform future disease monitoring strategies.

METHODS

This study integrated summary statistics from genome-wide association studies (GWAS) of two independent IBD cohorts and one PBC cohort, along with spatially resolved single-cell transcriptomic data. Genetic correlations were examined using linkage disequilibrium score regression, genetic covariance estimation, and localized variant association analyses. Shared susceptibility loci were identified through conditional/joint false discovery rate (FDR) approaches and multi-trait joint analysis. Furthermore, a genetic information-guided cell-type spatial mapping strategy was applied to delineate disease-associated cellular populations at single-cell resolution.

RESULTS

Genetic analyses revealed significant genome-wide correlations and extensive polygenic overlap between IBD, its subtypes, and PBC. Local variation analyses further identified multiple chromosomal regions exhibiting regional genetic associations shared by both diseases. Several putative shared susceptibility loci were discovered, with a subset validated using independent datasets. The genetic information-guided spatial mapping approach demonstrated comparable tissue-resident cell distribution patterns between IBD and PBC.

CONCLUSION

By integrating GWAS data with single-cell transcriptomic profiling, this study provides a systematic characterization of the genetic relationships between IBD and PBC. These findings offer genetic and cellular-level insights that contribute to a deeper understanding of the molecular basis underlying their comorbidity.