Multi-Omics Integrative Analysis Identifies the NK Cell–STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis

Primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) exhibit a striking clinical comorbidity, with 60–80% of PSC patients concurrently harboring UC, yet the shared immunogenetic mechanisms remain poorly understood. Here, we constructed a multi-omics integrative framework to systematically dissect the cellular and molecular basis of this comorbidity. GWAS meta-analyses were performed for each disease, followed by tissue-level enrichment assessment using QTLEnrich, MAGMA, and gsMap spatial mapping. Single-cell transcriptomic atlases were constructed, and cell-type prioritization was conducted using four complementary methods. Core genes were identified through cross-validation of five algorithms, with subsequent genomic fine-mapping via FUMA and GCTA-COJO. Tissue-level analyses consistently identified the intestine and immune-related tissues as commonly affected. Multi-dimensional evidence integration prioritized natural killer (NK) cells as the core effector cell type for both diseases, supported principally by CELLECT (Cell-type Expression-specific Integration for Complex Traits) heritability enrichment and single-cell differential analysis. Convergence of five gene-level algorithms pinpointed STAT3 as the sole high-confidence comorbidity gene, broadly expressed across immune cell populations and exhibiting tissue-differential alternative splicing. Colocalization identified a high-risk variant (rs3736161) within the STAT3 locus, with conditional analysis revealing 35 additional independent signals. These findings identify the NK cell–STAT3 axis as a central immunogenetic hub connecting PSC and UC, offering potential therapeutic targets for comorbidity management.