Multi-Omics Integration Reveals the Genetic Mechanisms of Periodontitis and Predicts Therapeutic Drugs.

BACKGROUND: Periodontitis is a chronic inflammatory disease driven by host immune dysregulation. However, the specific genetic regulatory mechanisms underlying this disease remain unclear. Identifying key molecular targets is crucial for precise therapeutic intervention. METHODS: This study integrated genome-wide association study (GWAS) summary statistics from the Gene-Lifestyle Interactions in Dental Endpoints and FinnGen R11 cohorts, with single-cell spatial transcriptomics and single-cell RNA sequencing profiles. The tissue-specific enrichment of these genetic signals was validated using genetically informed spatial mapping and QTL Enrichment analyses. Furthermore, this study employed methods such as single-cell pathway-based GWAS and single-cell Mendelian randomization to systematically dissect the genetic basis of periodontitis. An artificial intelligence-driven drug screening framework (DrugRefLector) and molecular docking were used to predict potential therapeutic compounds. RESULTS: Tissue-specific enrichment analysis revealed that periodontitis genetic signals were enriched not only in jawbone and teeth, but also significantly in tissues such as the brain and renal cortex. Multi-dimensional single-cell analysis identified monocytes and NK cells as key immune subsets and 23 genes causally associated with periodontitis. Among these, GNLY was prioritized as a computational lead, with evidence from multiple analytical approaches suggesting a potential role in linking innate immune recognition, cytotoxic effects, and tissue damage. The DrugReflector framework predicted 5 candidate compounds with therapeutic potential, all of which exhibited favorable binding affinities to GNLY in molecular docking simulations, providing a structural basis for subsequent drug optimization. CONCLUSION: This study develops a multi-layered analytical framework to systematically investigate the genetic architecture and key regulators of periodontitis. It provides candidate drugs and a theoretical foundation for targeted immunomodulatory therapies. CLINICAL RELEVANCE: The genetic enrichment in the brain and kidney provides a mechanistic basis for the systemic comorbidities of periodontitis, supporting the rationale for integrated oral-systemic health management.