Abstract: The comorbidity of skin and gastrointestinal tract (GIT) diseases, primarily driven by the gut-skin axis (GSA), is well-known. However, the genetic contribution to the GSA remains unclear. Here, using genome-wide association study (GWAS) summary statistics from European populations, we performed genome-wide pleiotropic analysis to investigate the shared genetic basis and causal associations between skin and GIT diseases. We observed extensive genetic correlations and overlaps between skin and GIT diseases. A total of 298 pleiotropic loci were identified, 75 of which were colocalized, and 61 exhibited pleiotropic effects across multiple trait pairs, including 2p16.1 (PUS10), 6p21.32 (HLA-DRB1), 10q21.2 (ZNF365), and 19q13.11 (SLC7A10). Additionally, five novel loci were identified based on the pleiotropic analysis, with RORA at 15q22.2 validated by the latest inflammatory bowel disease GWAS. Gene-based analysis found 394 unique pleiotropic genes, which were enriched in GSA-associated tissues and immune system, whereas protein-protein interaction analysis further revealed the GPCR-cAMP, chromatin remodeling, JAK-STAT, and HLA-mediated immunity pathways coregulate GSA comorbidity. Notably, the JAK-STAT pathway showed strong potential in drug repurposing, with Adalimumab targeting TNF and Ustekinumab targeting IL-12B already used to treat both skin and GIT diseases. Finally, Mendelian randomization analysis suggested five significant causal associations, and subsequent mediation analysis introduced three potential microbiota-GIT-skin pathways. Taken together, our study suggested that the shared genetic factors between skin and GIT diseases are widely distributed across the genome. These findings will improve our understanding of the genetic basis of GSA and offer significant implications for simultaneously treating skin and GIT diseases.