Shared genetic pathways linking oral diseases to gastrointestinal disorders: an integrative multi-omics study

Oral diseases are highly prevalent worldwide and are increasingly recognized to correlate with gastrointestinal conditions, yet the shared genetic basis and causal mechanisms of oral‑gut comorbidity remain poorly understood. This study integrated pleiotropy mapping, genetic colocalization, transcriptome‑wide (TWAS), proteome‑wide (PWAS) association analyses, bidirectional Mendelian randomization, and gene‑environment interaction analyses using large European‑ancestry GWAS summary statistics and UK Biobank individual‑level data.

Fourteen of fifteen pre‑specified oral‑gastrointestinal trait pairs showed significant genome‑wide genetic correlation. Researchers detected 400 candidate pleiotropic loci distributed across 390 chromosomal regions, with several genomic hotspots recurring across multiple disease pairs. Functional enrichment revealed these pleiotropic genes are strongly enriched for immune‑response and gastrointestinal signalling pathways. Colocalization, TWAS and PWAS further prioritised candidate genes and molecular signatures relevant to oral‑gut disease susceptibility.

Bidirectional two‑sample Mendelian randomization indicated periodontitis exerts a causal risk‑increasing effect on inflammatory bowel disease, whereas no reverse causal association was observed. Gene‑environment interaction results showed that modifiable lifestyle and psychological exposures significantly modify genetic risk for oral‑gut comorbidity.

This work delivers multi‑layer evidence for shared genetic pathways connecting oral and gastrointestinal disorders. While these results are hypothesis‑generating and limited primarily to European‑ancestry populations, they inform future functional validation, risk‑stratification strategies, and precision prevention research targeting the oral‑gut axis.