{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T06:19:19Z","timestamp":1783491559747,"version":"3.55.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Inflammatory bowel disease (IBD), including Crohn\u2019s 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LDSC showed strong positive genetic correlations among overall IBD, CD, and UC, including overall IBD versus CD (r\n                      <jats:sub>g<\/jats:sub>\n                      = 0.9458, P\u00a0=\u00a01.79 \u00d7 10\n                      <jats:sup>\u22128<\/jats:sup>\n                      ), overall IBD versus UC (estimated r\n                      <jats:sub>g<\/jats:sub>\n                      = 1.0907, P\u00a0=\u00a03.48 \u00d7 10\n                      <jats:sup>\u22126<\/jats:sup>\n                      ), and CD versus UC (r\n                      <jats:sub>g<\/jats:sub>\n                      = 0.9535, P\u00a0=\u00a00.0133). 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\u00a0=\u00a03.52 \u00d7 10\n                      <jats:sup>\u22127<\/jats:sup>\n                      , q = 1.41 \u00d7 10\n                      <jats:sup>\u22126<\/jats:sup>\n                      ), lamina propria (ACAT P\u00a0=\u00a02.75 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      , q = 4.27 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ), follicular clusters (ACAT P\u00a0=\u00a07.31 \u00d7 10\n                      <jats:sup>\u22127<\/jats:sup>\n                      , q = 1.10 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ), and myeloid clusters (ACAT P\u00a0=\u00a06.67 \u00d7 10\n                      <jats:sup>\u22126<\/jats:sup>\n                      , q = 3.34 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ). In GSE189184 idiopathic UC inflamed tissue, enrichment was observed in GWAS-independent immune-rich (ACAT P\u00a0=\u00a01.72 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      , q = 1.38 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), structural\/barrier (ACAT P\u00a0=\u00a07.52 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      , q = 3.01 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), epithelial-mucosal (ACAT P\u00a0=\u00a09.08 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      , q = 0.00182), inflammation-repair (ACAT P\u00a0=\u00a00.00140, q = 0.00224), and stromal-fibrotic domains (ACAT P\u00a0=\u00a00.00268, 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Shared IBD genetic liability was most consistently linked to an adult immune\u2013epithelial 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1853177","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:58:53Z","timestamp":1783490333000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial genetic mapping links shared inflammatory bowel disease liability to adult immune\u2013epithelial lesion contexts"],"prefix":"10.3389","volume":"17","author":[{"given":"Guangyi","family":"Tao","sequence":"first","affiliation":[{"name":"Guangxi University of Chinese Medicine","place":["Nanning, 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