Shared Genetic Pathways Linking Oral Diseases to Gastrointestinal Disorders: An Integrative Multi‐Omics Study

ABSTRACT Oral diseases are highly prevalent and increasingly recognized as contributors to gastrointestinal disorders. Despite clinical observations of oral–gut comorbidity, the underlying genetic architecture and causal mechanisms remain poorly understood. In this study, we analyzed genome‐wide association summary statistics for three oral diseases and five gastrointestinal disorders, integrating pleiotropy mapping, colocalization, transcriptome‐ and proteome‐wide association studies, and bidirectional Mendelian randomization. Our analyses identified 400 candidate pleiotropic loci across 390 chromosomal regions, with three loci repeatedly observed across trait pairs. Functional annotation revealed significant enrichment of pleiotropic genes in immune and gastrointestinal pathways, while colocalization and multi‐omics analyses prioritized candidate genes and molecular associations for further investigation. Bidirectional Mendelian randomization indicated that oral diseases causally increase the risk of IBD, while no reverse causal effects were observed. And gene–environment interactions provided evidence that diet, body mass index, physical activity, smoking, and mental health significantly modulate genetic susceptibility ( p < 0.05). These findings provide comprehensive evidence of shared genetic architecture and potential causal associations, offering insights for understanding oral–gut comorbidity and generating hypotheses for future translational studies.