<p>Previous studies have suggested a comorbidity between psoriasis (PSO) and immune-mediated gastrointestinal (GI) diseases; however, the underlying genetic correlations and mechanisms remain unclear. This study aimed to elucidate the shared genetic architecture and biological mechanisms between PSO and immune-mediated GI diseases, providing insights for precision treatment strategies. We integrated publicly available GWAS summary statistics for PSO and multiple immune-mediated GI diseases, including Crohn’s disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease (COELIAC), and chronic gastritis (CG). Linkage Disequilibrium Score Regression (LDSC) and High-Definition Likelihood (HDL) estimation were employed, while bidirectional Mendelian Randomization (MR) was used to investigate causal relationships. Cross-phenotype analyses were employed to identify shared loci and genes, integrating Pleiotropy Analysis Under the Composite Null Hypothesis (PLACO) and Functional Mapping and Annotation (FUMA), followed by Multi-marker Analysis of Genomic Annotation (MAGMA). The Summary-data-based Mendelian Randomization (SMR) method combined GWAS summary-level data with expression quantitative trait loci (eQTL) studies to pinpoint genes whose expression mediated the observed associations. Potential drug interventions targeting pleiotropic genes were predicted using the DSigDB database. Genetic enrichment analysis was performed to identify key cell types and tissues, and shared immune-related phenotypes were delineated through Hypothesis Prioritisation in multi-trait Colocalization (HyPrColoc). Significant genetic correlations between PSO and immune-mediated GI diseases were confirmed by genome-wide analyses using LDSC and HDL, while bidirectional MR indicated potential causal relationships. Cross-trait pleiotropic analysis using PLACO and FUMA identified 113 pleiotropic loci, including 35 shared across trait combinations (e.g., 5q33.3, 2p16.1, 5q31.1). Identification and enrichment analysis of shared pathogenic genes, performed using SMR and MAGMA, revealed 38 pleiotropic genes, notably PEX13, RGS14, and C5orf56, which were involved in peroxisome homeostasis, lymphocyte adhesion and migration, and Th1/Th2 immune balance, respectively. Pathway enrichment highlighted lymphocyte differentiation, immune activation, and intercellular adhesion. Shared genetic signals exhibited strong tissue and cell-type specificity, particularly in the spleen, whole blood, EBV-transformed lymphocytes, bone marrow B cells, and spleen T cells. Finally, potential therapeutic targets were predicted using DSigDB, providing valuable insight into targeted treatment strategies. This study systematically, for the first time, reveals the shared genetic structure between PSO and immune-mediated GI diseases, identifying novel pleiotropic loci and functional genes, laying the foundation for understanding comorbid disease mechanisms, and developing targeted therapeutic strategies.</p>