Dissecting Smoking-Related and Smoking-Independent Genetic Components of Periodontitis

Objectives Periodontitis (PD) is a prevalent chronic inflammatory disease with substantial global burden, yet its genetic architecture remains incompletely understood. Although smoking is a major risk factor, many individuals develop PD without smoking exposure, suggesting biologically distinct pathogenic pathways. This study aimed to disentangle the genetic architecture underlying smoking-related and smoking-independent PD and to characterize their distinct biological mechanisms. Methods We applied a genome-wide association study-by-subtraction framework to summary statistics from 2669,029 individuals to partition PD into smoking-related and smoking-independent genetic components. Integrative analyses included Bayesian fine-mapping, transcriptome-wide and proteome-wide association analyses, colocalization, neuroimaging-informed association analyses, and integration with gingival single-cell transcriptomic data. Results The smoking-related component indicated extensive polygenic architecture, identifying 287 independent loci and widespread molecular associations. In contrast, the smoking-independent component showed markedly fewer signals, including one genome-wide significant locus and a limited number of candidate genes. FOXO3 and MST1 were consistently prioritized in the smoking-related component, implicating oxidative stress, immune regulation, and neurobehavioural pathways. Conversely, AGER emerged as the principal candidate gene in the smoking-independent component, suggesting distinct inflammatory mechanisms. Neuroimaging analyses further linked smoking-related genetic liability to brain regions involved in reward and behavioural regulation. Conclusions Our findings highlight distinct smoking-related and smoking-independent genetic components of PD that may be obscured in conventional genetic analyses. These findings provide new insights into the heterogeneous genetic architecture of PD, prioritize candidate genes for future functional investigation, and may inform future genetically informed risk assessment, precision prevention, and host-modulating therapeutic strategies.