Materials and Methods: Using summary data from genetic association studies from up to 1.1 million participants of European descent, univariable and multivariable Mendelian randomization analyses were performed to infer the total effect of educational attainment on periodontitis and to estimate the degree to which income, smoking, alcohol consumption, and body mass index mediate the association. Results:The odds ratio of periodontitis per 1 standard deviation increment in genetically predicted education was 0.78 (95% CI: 0.68-0.89). The proportions mediated of the total effect of genetically predicted education on periodontitis were 64%, 35%, 15%, and 46% for income, smoking, alcohol consumption, and body mass index, respectively.Conclusions: Using a genetic instrumental variable approach, this study triangulated evidence from existing observational epidemiological studies and suggested that higher educational attainment lowers periodontitis risk. Measures to reduce the burden of educational disparities in periodontitis risk may tackle downstream risk factors, particularly income, smoking, and obesity.

BackgroundObservational and in-vivo research suggested a bidirectional relationship between depression and periodontitis. We estimated the genetic correlation and examined directionality of causation.MethodsThe study used summary statistics from published genome wide association studies, with sample sizes ranging from 45,563 to 797,563 individuals of European ancestry. We performed linkage disequilibrium score regression (LDSC) to estimate global correlation and used Heritability Estimation from Summary Statistics (ρ-HESS) to further examine local genetic correlation. Latent Heritable Confounder Mendelian randomization (LHC-MR), Causal Analysis using Summary Effect estimates (CAUSE), and conventional MR approaches assessed bidirectional causation.ResultsLDSC observed only weak genetic correlation (rg = 0.06, P-Value = 0.619) between depression and periodontitis. Analysis of local genetic correlation using ρ-HESS did not reveal loci of significant local genetic covariance. LHC-MR, CAUSE and conventional MR models provided no support for bidirectional causation between depression and periodontitis, with odds ratios ranging from 1.00 to 1.06 in either direction.ConclusionsResults do not support shared heritability or a causal connection between depression and periodontitis.

Background:The purpose of the study was to examine the association between total body bone mineral density (BMD) and periodontitis using Mendelian randomization (MR) analysis. Methods and materials:We used 81 single nucleotide polymorphisms (SNPs) associated with BMD at a p-value of < 5 × 10 −8 from a genome-wide association study (GWAS) of 66,628 individuals of European descent. The GWAS for periodontitis was derived from a meta-analysis of seven cohort studies that included 17,353 cases and 28,210 controls of European ancestry. Results: MR showed no association between BMD and periodontitis (odds ratio per standard deviation increment in genetically predicted BMD = 1.00; 95% confidence interval: 0.92-1.08). Leave-one-out analyses and pleiotropy-robust methods did not indicate any bias. Conclusions:The MR study provided no evidence that BMD might be causally linked to periodontitis. Hence it may be concluded as the key finding that BMD depletion does not increase the risk of periodontitis.

Background: Twenty five-hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long-term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR).Methods: Genetic variants strongly associated with 25OHD in a genome-wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome-wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97. Results: MR analysis suggested that a 1 standard deviation increase in natural log-transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97-1.12; P-value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis.

Aim Epidemiological and pre‐clinical studies suggest a chemoprotective role of lipid‐lowering agents in periodontitis. We tested the association of genetically proxied inhibition of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR), Niemann‐Pick C1‐Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) with periodontitis. Materials and Methods Genetic variants in HMGCR, NCP1L1 and PCSK9 associated with low‐density lipoprotein (LDL) cholesterol in a genome‐wide association study (GWAS) meta‐analysis (N = 188,578) were used to proxy therapeutic inhibition of HMGCR, NPC1L1 and PCSK9. For these genetic variants, associations with periodontitis were obtained from GWAS of 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. Generalized weighted least squares analysis accounted for linkage disequilibrium of genotypes to derive pooled estimates. Results While genetically proxied HMGCR inhibition equivalent to 1 mmol/L reduction in LDL was not associated with odds of periodontitis (odds ratio [OR] = 0.92 [95% confidence interval [CI]: 0.73; 1.16]; p = .4905; false discovery rate [FDR] = 0.4905), genetically proxied NPC1L1 (OR = 0.53 [95% CI: 0.35; 0.81]; p = .0038; FDR = 0.0077) and PCSK9 (OR = 0.84 [95% CI: 0.74; 0.95]; p = .0051; FDR = 0.0077) inhibition lowered the odds of periodontitis. Conclusions Genetically proxied inhibition of NCP1L1 and PCSK9 was associated with lower odds of periodontitis.