Abstract Background More than 90% of Crohn’s disease (CD)–associated genomic loci reside in non–protein-coding regions, limiting their biological interpretation and clinical application. Understanding how these variants regulate intestinal gene expression across populations is essential to link genetic risk into disease mechanisms and guide precision medicine. Methods We performed a cross-ancestry intestinal transcriptomic analysis integrating six cohorts spanning China, Europe and North America (CD = 1,262; controls = 332; total samples = 3,012), including both inflamed and non-inflamed biopsies. A molecular inflammatory score (MIS) combining gene-, isoform-, and splicing-level features was developed to assess disease activity. To identify genetic effects on these molecular features, 7.8 million genetic variants from four cohorts (samples = 1,182) were incorporated for quantitative trait locus (QTL) mapping using multivariable mixed linear regression models. Cross-ancestry and ancestry-specific QTLs were determined through random-effect meta-analysis and heterogeneity testing. Inflammation-dependent QTLs were examined by interaction models. Multi-omics integration, including GWAS summary statistics, single-cell RNAseq, and ChIP/CLIP datasets, was performed to explore regulatory mechanisms. Results In total, 15,730 genes, 32,991 isoforms and 3,235 splicing events were identified across six cohorts. The MIS showed significant associations with disease activity across Chinese and European patients. QTL mapping revealed 12,026 transcriptomic features under genetic regulation shared across ancestries, explaining 6–12% of the estimated genetic liability to CD and providing regulatory mechanisms for ∼60% of CD-associated GWAS loci. Enrichment analysis demonstrated that ancestry-specific QTLs were mainly driven by allele-frequency differences (P 2.2 × 10-16). For example, at the TNFSF15 locus, a variant with G-allele was more frequent in Chinese individuals. This variant induced intron retention through disrupting the spliceosome binding site (false discovery rate, FDR =2.1 × 10-4), generating a variant transcript associated with increased disease activity. Genetic signals associated with inflammation-dependent regulation were most pronounced in intestinal epithelial progenitor and immune cell populations, particularly macrophages and CD4+ T cells. Conclusion This study establishes the largest cross-ancestry intestinal genetic regulatory map to date, bridging CD-associated GWAS loci to functional consequences in disease-relevant tissue. These findings reveal ancestry-informed regulatory mechanisms and inflammation-specific genetic effects that may advance precision diagnostics and personalized therapeutic strategies. Conflict of interest: Hu, Shixian: Grant: Natural Science Foundation of China 8257063982300623GuangDong Basic and Applied Basic Research Foundation 2025B1515020059 Su, Fengyuan: NA Wang, Yuanmei: NA Wang, Yu: NA Xiong, Shanshan: NA Lin, Sinan: NA Li, Xiaozhi: NA Tie, Yizhe: NA Jansen, Bernadien: NA Tang, Ce: NA Feng, Rui: NA Ramnik, Xavier: NA Dijkstra, Gerard: Grant: Royal DSM Personal Fees: Consultancy fee from Astra-Zeneca and Speakers fee from Abbvie Festen, Eleonora: NA Gacesa, Ranko: Grant: Partially funded by Janssen Pharmaceuticals (for projects unrelated to any of research presented at this conference) Personal Fees: Paid freelance consulting for Esox biologicals ltd. (for projects unrelated to any of research presented at this conference) Bourgonje, Arno R.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work. Chen, Minhu: I have received speaker honoraria from Takeda China, Xian Janssen, and AbbVie China, as well as research funding from Takeda (China). Weersma, Rinse K: NA Mao, Ren: NA
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