Multivariable genome-wide analysis elucidates the shared genetic architecture, immunosenescence features, and gut-origin therapeutic targets of ulcerative colitis-associated multisystem inflammation.

backgroundOver 25% of patients with ulcerative colitis (UC) develop extraintestinal manifestations (EIMs), resulting in significant systemic morbidity. We define the shared genetic foundation of these manifestations as the UC-associated Multisystem Inflammatory Genetic Architecture (UC-MIGA). This study aims to identify shared genomic drivers and actionable immunosenescence therapeutic targets across the UC-EIM spectrum.

methodsWe applied genomic structural equation modeling (SEM) to seven European-ancestry GWAS datasets (UC, deep vein thrombosis, ankylosing spondylitis, primary sclerosing cholangitis, pyoderma gangrenosum, interstitial lung disease, and erythema nodosum) to identify a shared latent genetic factor (F1). Post-SEM analyses included FUMA mapping, SuSIE/FINEMAP fine-mapping, FUSION/FOCUS transcriptome-wide studies, MAGMA enrichment, CELLECT deconvolution, LDSC partitioned heritability, and single-cell eQTL Mendelian randomization (MR). UC exhibited the highest standardized factor loading (0.9801) on F1, justifying its use as a representative proxy for UC-MIGA in downstream analyses. UC-telomere relationships were assessed via tissue-specific eQTL/sQTL enrichment across 49 GTEx tissues, spatial transcriptomics (gsMap), single-cell profiling (GSE214695, GSE163974), hdWGCNA, and colocalization analyses (eCAVIAR, fastENLOC).

resultsSEM identified substantial genetic overlap (CFI = 1.0, SRMR = 0.17). Within the UC-MIGA framework, we identified 17,005 SNPs (P ≤ 1 × 10⁻2⁰⁰), 2,622 risk loci, and 152 high-confidence effector genes. Pathways implicated Th17/Treg imbalance and inflammasome signaling. Super-enhancer regions showed exceptional heritability enrichment (80.16%, fold = 4.79, p = 0.0007). MR identified 35 causal immune cell-gene associations. UC-telomere analyses revealed convergence in colon-specific DNA repair-mitochondrial energetics-telomere maintenance pathways, with B cells prioritized as the core cell type. Colocalization identified NKX2-3 and LINC01475 as high-confidence shared candidates. Embryonic intestinal enrichment supported the developmental origins of this systemic axis.

conclusionUC-MIGA represents a genetically coherent architecture driven by super-enhancer-mediated epigenetic dysregulation, Th17/Treg imbalance, and immunosenescence features, including telomere dysfunction and B-cell exhaustion. The 'developmental vulnerability-environmental trigger' model explains the gut-origin inflammatory cascade underlying extraintestinal manifestations, with UC-telomere analysis providing a genomic foundation for systemic therapeutic strategies targeting the inflammation-aging nexus.