Genomic Structural Equation Modelling Reveals the Shared Genetic Architecture for Oral Frailty

Oral frailty, an age-related decline in oral function and health linked to adverse geriatric outcomes, involves multiple phenotypes. Chronic periodontitis, a key inflammatory driver of tooth loss and systemic disease, is a cornerstone of this syndrome, yet the shared genetic architecture connecting it to other oral conditions remains uncharacterised.

We employed genomic structural equation modelling (genomic SEM) to integrate genome-wide association studies (GWAS) summary statistics from five oral frailty-related phenotypes, defining a common latent factor reflecting their shared genetics. We further integrated several post-GWAS analytical methods, including locus and gene discovery (MAGMA, TWAS/FOCUS), fine-mapping (SuSiE, FINEMAP), pathway and cell-type enrichment (S-LDSC, CELLECT), spatial mapping (gsMap), and Polygenic Risk Score analyses.

The genomic SEM model demonstrated a good fit and revealed a common genetic factor underlying oral frailty. We identified four genome-wide significant loci, three of which are novel for oral frailty. Fine-mapping prioritised rs150699482 (KIAA0247), rs78975199 (SPG11), and rs2705755 (SNORA77) as likely causal variants. MAGMA highlighted 13 candidate susceptibility genes, with SPG11 and CCDC91 among the top candidates. TWAS and FOCUS analyses robustly implicated RP11-967K21.1 as a putative causal gene. Cell-type enrichment analysis indicated significant involvement of brain endothelial cells, immune cells, and mammary gland stromal cells. Heritability was enriched in evolutionarily conserved regions and active regulatory elements. Notably, gsMap analysis showed that genetic risk for oral frailty is enriched not only in jaw and tooth tissues but also across multiple embryonic tissues, including adipose tissue, dorsal root ganglion, mucosal epithelium, and connective tissue.

This study provides the first comprehensive genomic SEM-based characterisation of the shared architecture underlying oral frailty-related traits. By demonstrating a common genetic basis linking periodontitis with other oral dysfunctions, it provides novel insights into shared aetiological pathways and reinforces the concept of oral frailty as a systemic issue.