A Cross‐Tissue Transcriptome‐Wide Association Study Reveals Novel Susceptibility Genes for Inflammatory Bowel Disease

ABSTRACT Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is an autoimmune disease with a strong genetic component. Although genome‐wide association studies (GWAS) have identified multiple risk loci, the underlying causal genes and biological mechanisms remain predominantly elusive. GWAS data for IBD, UC, and CD were obtained from the FinnGen R10 dataset and integrated with expression quantitative trait locus (eQTL) data from the Genotype‐Tissue Expression Project (GTEx) v8 to perform cross‐tissue transcriptome‐wide association studies (TWAS). Single‐tissue TWAS validation was conducted using Functional Summary‐based Imputation (FUSION). Multi‐marker Analysis of GenoMic Annotation (MAGMA), Mendelian randomization (MR), colocalization, and summary data‐based MR (SMR) analyses were applied to identify candidate susceptibility genes. GeneMANIA analysis was performed to explore functional implications. The same analytical framework was used on independent GWAS datasets to assess consistency. 6 susceptibility genes were identified for IBD, 1 for UC, and 2 for CD. These findings were supported by cross‐ and single‐tissue TWAS, MAGMA, MR, colocalization, and SMR analyses. In independent datasets, partial gene‐level concordance and substantial consistent pathway‐level signals were observed. GeneMANIA analyses suggested that susceptibility genes in IBD, UC, and CD were mainly associated with 3′,5′‐cyclic‐nucleotide phosphodiesterase activity, transition metal ion transmembrane transporter activity, and CENP‐A–containing chromatin organization, respectively. By integrating cross‐tissue TWAS with multi‐tier validation strategies, this study provides new insights into the genetic architecture of IBD. Further functional studies are necessary to elucidate the mechanisms by which these candidate genes contribute to IBD pathogenesis.