From the Oral Microbiome to Periodontitis: Bioinformatics Identifies ANK3

Background Oral microbiome (OM) dysbiosis is associated with periodontitis, but its causal relevance and the biological mechanisms of periodontal tissue destruction remain unclear. Materials and methods Bidirectional Mendelian randomization (MR) assessed causal associations of species-level tongue dorsum and salivary microbiome traits with periodontal disease using East Asian genome-wide association study (GWAS) data. Candidate genes mapped from MR instruments were prioritized based on overlap with differentially expressed genes (DEGs), module genes identified by weighted gene co-expression network analysis (WGCNA), and eQTLGen-based MR findings. The candidate gene was further evaluated by MR using East Asian cis-expression quantitative trait locus (cis-eQTL) data and European-ancestry genome-wide association study (GWAS) data for periodontitis subtypes. Single-cell RNA sequencing and spatial transcriptomics examined its cellular role. Phenome-wide association study (PheWAS) and drug–target interaction prediction assessed on-target safety. Results Forward MR identified 46 species-level taxa associated with periodontal disease, enriched in Campylobacter_A , Fusobacterium , and Streptococcus ; reverse MR identified 47 taxa, mainly in Prevotella and Streptococcus . Intersection analysis identified ANK3 , which was downregulated in periodontitis. MR consistently supported a protective causal effect of ANK3 on periodontitis across cohorts. Single-cell analysis showed predominant ANK3 expression in periodontal ligament stem cells (PDLSCs), with reduced expression in periodontitis. Spatial transcriptomics showed overlap of ANK3 -enriched PDLSC regions with periodontitis genetic risk signals. PheWAS and drug–target interaction prediction revealed no major on-target safety concerns. Conclusions These findings link causally relevant OM features to ANK3 –related PDLSC vulnerability in periodontitis and identify a potential host cellular axis for further investigation.