Multivariate GWAS reveals shared genetic basis of common oral diseases

Background: Oral diseases, including dental caries, periodontitis, pulpitis, and temporomandibular disorders (TMD), impose a substantial global burden affecting billions of individuals and costing an estimated USD 390 billion annually. Despite their frequent clinical co-occurrence, the extent to which these conditions share a common genetic basis remains unclear. Methods: We analyzed genome-wide association study (GWAS) summary statistics from up to 500,000 Finnish participants. Genome-wide and regional genetic correlations were quantified using High-Definition Likelihood. Genomic Structural Equation Modelling was applied to identify a latent common oral genetic factor (COF). A multivariate GWAS of the COF was conducted, followed by SuSiE fine-mapping. Integrative gene and pathway analyses were performed using cTWAS and MAGMA, and spatial mapping was conducted using embryonic tooth-germ atlases. Results: We identified extensive shared heritability across all four oral diseases. A latent COF captured the majority of this genetic overlap. Multivariate GWAS of the COF identified 104 genome-wide significant single-nucleotide polymorphisms aggregated into 96 independent loci, which were largely novel compared to single-trait analyses. Fine-mapping refined these to 53 high-confidence causal variants enriched in immune-regulatory and odontogenic pathways. CPSF1 and SLC20A2 emerged as top-ranked genes, with tissue-specific effects mapped to coronary artery and cultured fibroblasts, respectively. Spatial projection localized genetic risk to follicular and mesenchymal compartments, consistent with developmental tissue differentiation patterns. Conclusion: These findings reveal a shared and developmentally rooted genetic architecture underlying common oral diseases. The results highlight convergent molecular mechanisms and provide a foundation for precision-based, integrated prevention strategies that move beyond traditional single-disease frameworks.