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.