Genomic correlation, shared loci, and causal association between obesity, periodontitis and tooth loss

Observational studies have reported an association of obesity with periodontitis and tooth loss, yet findings remain inconsistent. We aim to investigate the genetic link underlying obesity-related traits (BMI [body mass index], WHR [waist-to-hip ratio], WHR_adjBMI and childhood BMI), periodontitis and tooth loss. Leveraging summary statistics from large-scale genome-wide association studies, we comprehensively investigated the pair-wise genetic correlation using linkage disequilibrium score regression (LDSC) and SUPERGNOVA, identified shared loci using cross-phenotype association analysis (CPASSOC), and estimated causal association using Mendelian randomization. We identified a significant genetic correlation of obesity with tooth loss, but not with periodontitis. Partitioning the genome into LD-independent regions revealed 10 significantly shared local signals across six regions. Genome-wide cross-trait analysis uncovered 14 shared loci, four of which were colocalized: rs2064044 (PP4 = 0.94), rs6000329 (PP4 = 0.86), rs7134628 (PP4 = 0.86), and rs1286769 (PP4 = 0.90). Notably, rs1286769, identified via CPASSOC and validated through colocalization analysis, is located near RARβ, a gene associated with both BMI and denture use. Mendelian randomization revealed a nominally-significant causal association of obesity with periodontitis (P = 0.045) but a robust causal association with tooth loss represented by number of teeth (BMI: beta = [Formula: see text]0.20, 95%CI = [Formula: see text]0.26 to [Formula: see text]0.14, P = 5.27 × 10^-11; WHR: beta = [Formula: see text]0.16, 95%CI = [Formula: see text]0.24 to [Formula: see text]0.08, P = 3.71 × 10^-5). Results of CAUSE were consistent with main findings. From a genetic perspective, our work highlights an intrinsic link between obesity, periodontitis and tooth loss, which may add new lines of evidence and provide insights for clinical and public oral health applications.