Frontiers in immunology · 2026
Spatial genetic mapping links shared inflammatory bowel disease liability to adult immune-epithelial lesion contexts.
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Tao Guangyi, Du Hanzhe, Zhao Jun, Zeng Zhonghe, Cui Junwu, Lei Longming
Аннотация
BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), shows marked clinical heterogeneity despite a shared immune-genetic background. The adult spatial contexts through which inherited IBD susceptibility is expressed remain unclear.
METHODS: We integrated GWAS summary statistics for overall IBD, CD, and UC with LDSC, stratified LDSC, LDSC-SEG, MAGMA, PoPS, and genetically informed spatial mapping (gsMap). Human genetic signals were projected onto the E16.5 mouse single-cell spatial atlas as an exploratory developmental reference, and adult disease-tissue spatial support was assessed across SCP2959 CD spatial sections and GSE189184 idiopathic UC inflamed Visium sections. PoPS-independent MAGMA-only module-score and FUSION-TWAS sensitivity analyses, together with targeted RT-qPCR in NCM460 epithelial cells and THP-1-derived macrophage-like cells were performed.
RESULTS: LDSC showed strong positive genetic correlations among overall IBD, CD, and UC, including overall IBD versus CD (rg = 0.9458, P = 1.79 × 10-8), overall IBD versus UC (estimated rg = 1.0907, P = 3.48 × 10-6), and CD versus UC (rg = 0.9535, P = 0.0133). MAGMA and PoPS prioritized immune-inflammatory candidates, including IL23R, JAK2, STAT3, CCL2, NOD2, and HLA-region genes. Exploratory developmental gsMap showed nominal signals in gastrointestinal, liver, smooth-muscle, epidermal, and neural regions. In adult disease-tissue gsMap, overall IBD signals showed FDR-significant enrichment in SCP2959 CD immune regions (ACAT P = 3.52 × 10-7, q = 1.41 × 10-6), lamina propria (ACAT P = 2.75 × 10-5, q = 4.27 × 10-5), follicular clusters (ACAT P = 7.31 × 10-7, q = 1.10 × 10-5), and myeloid clusters (ACAT P = 6.67 × 10-6, q = 3.34 × 10-5). In GSE189184 idiopathic UC inflamed tissue, enrichment was observed in GWAS-independent immune-rich (ACAT P = 1.72 × 10-5, q = 1.38 × 10-4), structural/barrier (ACAT P = 7.52 × 10-5, q = 3.01 × 10-4), epithelial-mucosal (ACAT P = 9.08 × 10-4, q = 0.00182), inflammation-repair (ACAT P = 0.00140, q = 0.00224), and stromal-fibrotic domains (ACAT P = 0.00268, q = 0.00357). MAGMA-only module-score and FUSION-TWAS sensitivity analyses provided PoPS-independent support for the adult lesion-context interpretation. RT-qPCR showed that JAK2 knockdown reduced cytokine-induced CCL2 and CXCL8 by 52.6% and 36.9% and partially restored OCLN expression, while LPS induced IL1B, TNF, CCL2, and PYCARD in macrophage-like cells.
CONCLUSION: Shared IBD genetic liability was most consistently linked to an adult immune-epithelial inflammatory lesion program involving immune-rich, epithelial-inflammatory, myeloid/follicular, lamina propria, structural/barrier, and remodeling-associated contexts. Developmental and subtype-weighted spatial signals, including neural-related signals in the embryonic reference, should be viewed as hypothesis-generating clues to developmental and neuroimmune programs rather than definitive subtype-specific mechanisms.
METHODS: We integrated GWAS summary statistics for overall IBD, CD, and UC with LDSC, stratified LDSC, LDSC-SEG, MAGMA, PoPS, and genetically informed spatial mapping (gsMap). Human genetic signals were projected onto the E16.5 mouse single-cell spatial atlas as an exploratory developmental reference, and adult disease-tissue spatial support was assessed across SCP2959 CD spatial sections and GSE189184 idiopathic UC inflamed Visium sections. PoPS-independent MAGMA-only module-score and FUSION-TWAS sensitivity analyses, together with targeted RT-qPCR in NCM460 epithelial cells and THP-1-derived macrophage-like cells were performed.
RESULTS: LDSC showed strong positive genetic correlations among overall IBD, CD, and UC, including overall IBD versus CD (rg = 0.9458, P = 1.79 × 10-8), overall IBD versus UC (estimated rg = 1.0907, P = 3.48 × 10-6), and CD versus UC (rg = 0.9535, P = 0.0133). MAGMA and PoPS prioritized immune-inflammatory candidates, including IL23R, JAK2, STAT3, CCL2, NOD2, and HLA-region genes. Exploratory developmental gsMap showed nominal signals in gastrointestinal, liver, smooth-muscle, epidermal, and neural regions. In adult disease-tissue gsMap, overall IBD signals showed FDR-significant enrichment in SCP2959 CD immune regions (ACAT P = 3.52 × 10-7, q = 1.41 × 10-6), lamina propria (ACAT P = 2.75 × 10-5, q = 4.27 × 10-5), follicular clusters (ACAT P = 7.31 × 10-7, q = 1.10 × 10-5), and myeloid clusters (ACAT P = 6.67 × 10-6, q = 3.34 × 10-5). In GSE189184 idiopathic UC inflamed tissue, enrichment was observed in GWAS-independent immune-rich (ACAT P = 1.72 × 10-5, q = 1.38 × 10-4), structural/barrier (ACAT P = 7.52 × 10-5, q = 3.01 × 10-4), epithelial-mucosal (ACAT P = 9.08 × 10-4, q = 0.00182), inflammation-repair (ACAT P = 0.00140, q = 0.00224), and stromal-fibrotic domains (ACAT P = 0.00268, q = 0.00357). MAGMA-only module-score and FUSION-TWAS sensitivity analyses provided PoPS-independent support for the adult lesion-context interpretation. RT-qPCR showed that JAK2 knockdown reduced cytokine-induced CCL2 and CXCL8 by 52.6% and 36.9% and partially restored OCLN expression, while LPS induced IL1B, TNF, CCL2, and PYCARD in macrophage-like cells.
CONCLUSION: Shared IBD genetic liability was most consistently linked to an adult immune-epithelial inflammatory lesion program involving immune-rich, epithelial-inflammatory, myeloid/follicular, lamina propria, structural/barrier, and remodeling-associated contexts. Developmental and subtype-weighted spatial signals, including neural-related signals in the embryonic reference, should be viewed as hypothesis-generating clues to developmental and neuroimmune programs rather than definitive subtype-specific mechanisms.