Cross-trait genomic and sequential analyses of multiple omics datasets identified shared genetic components for the gut–eye axis

The gut–eye axis (GEA) has been proposed as a framework for understanding comorbidity between gastrointestinal and ocular diseases. This study aimed to investigate their shared genetic architecture, pleiotropy, and putative biological pathways potentially influenced by environmental exposures and gut microbiota. This study integrated large-scale genome-wide association study summary data on five gastrointestinal and eight ocular diseases to assess genetic correlations and genetic overlap. Pleiotropic variants were identified, followed by functional and tissue-specific analyses. Gene–environment (G×E) interactions were evaluated using UK Biobank data. Mendelian randomization (MR) and mediation analyses were adopted to assess statistically inferred associations and potential mediating relationships involving gut microbiota. Extensive genetic correlations were identified between 40 trait pairs. In total, 366 pleiotropic loci were identified, with 21 loci showing evidence of colocalized shared signals. Notably, 2p21, 4q24, 19q13.32 and 5p15.31 were colocalized across 2 trait pairs, highlighting them as recurrent pleiotropic loci of potential interest. Of the 603 genes associated with pleiotropic variants, 261 recurred across two or more trait pairs. These genes were enriched in immune and inflammatory pathways and included well-known loci such as HLA-B and RBFOX1. Twenty-six pleiotropic variants interacted with 16 modifiable exposures (e.g., diet, mental health, BMI, smoking, physical activity), suggesting that G×E interactions may contribute to gut–eye comorbidity risk. Bidirectional MR identified 11 genetically predicted associations, while mediation analysis suggested a potential statistical association involving the polyamine biosynthesis pathway in the relationship between gastroesophageal reflux disease and diabetic retinopathy. This study characterizes shared genetic and environmental architecture across GEA-related disorders and highlights putative contributions from immune-related pathways and gut microbiota to disease comorbidity. Our findings provide a hypothesis-generating framework for future replication and experimental validation.