Fig. 1

Workflow of the study. A series of analyses was conducted to identify candidate causal oxidative stress (OS) genes associated with Crohn’s disease (CD) onset. OS-related genes were extracted from the GeneCards database. Six intestinal transcriptome datasets including patients with CD and healthy controls (HCs) were obtained from the GEO database and meta-analyzed to identify differentially expressed CD-related OS genes, followed by cell type-specific expression analysis (CSEA). Integration of GWAS summaries and cis-eQTLs/cis-mQTLs data from the blood by using three-step SMR methods prioritized putative blood OS genes and their regulatory elements associated with the risk of CD (SMR FDR < 0.05; HEIDI test P > 0.05). Sensitivity analyses were performed after the primary SMR to test the heterogeneity (Cochran Q statistic implemented in MR-Egger and inverse variance weighting (IVW) method, P > 0.05 indicates no heterogeneity exists). Moreover, we meta-analyzed the intestinal cis-eQTLs from two public summaries (GTEx and 1000IBD) and further integrated the meta-intestinal cis-eQTLs with fecal mbQTLs from the Dutch Microbiome Project (DMP) to uncover the potential interactions between OS genes and gut microbiota through SMR, sensitivity, and colocalization analysis (SMR FDR < 0.05; HEIDI test P > 0.05; Cochran Q P > 0.05; colocalization PPH4 > 0.5). An external First Affiliated Hospital of Sun Yat-sen University (FAH-SYS) inflammatory bowel disease (IBD) multi-omics cohort with paired intestinal bulk RNA-seq and fecal metagenomics data was used to validate the differentially expressed genes (DEGs). The directional associations between colocalized gene-microbiota were investigated as complementary evidence of OS gene-microbiota interactions