Cross-phenotype genome-wide association study supports shared genetic etiology between skin and gastrointestinal tract diseases

The comorbidity of skin and gastrointestinal tract (GIT) diseases, primarily driven by the gut-skin axis (GSA), is well established. However, the genetic contribution to the GSA remains unclear. Here, using genome-wide association study (GWAS) summary statistics from European populations, we performed a 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 ( <i>PUS10</i>), 6p21.32 ( <i>HLA-DRB1</i>), 10q21.2 ( <i>ZNF365</i>), and 19q13.11 ( <i>SLC7A10</i>). Additionally, five novel loci were identified based on the pleiotropic analysis; among them, the 15q22.2 locus harboring <i>RORA</i> was validated by the latest inflammatory bowel disease GWAS. Gene-based analysis identified 394 unique pleiotropic genes, which were enriched in GSA-associated tissues and the immune system, and protein-protein interaction analysis further revealed that the GPCR-cAMP, chromatin remodeling, JAK-STAT, and HLA-mediated immunity pathways were involved in GSA comorbidity. Notably, the JAK-STAT pathway showed strong potential for drug repurposing, with adalimumab targeting tumor necrosis factor and ustekinumab targeting interleukin-12 subunit beta already being used to treat both skin and GIT diseases. Finally, Mendelian randomization analysis identified five significant causal associations, and subsequent mediation analysis identified three potential microbiota-GIT-skin pathways. Taken together, our study demonstrated that the shared genetic factors between skin and GIT diseases were widely distributed across the genome. These findings will enhance our understanding of the genetic mechanisms underlying GSA comorbidity.