Causal effects of life course adiposity on temporomandibular disorders: A Mendelian randomization study.

BACKGROUND: Previous studies investigated the associations between obesity and temporomandibular disorders (TMDs), but the evidence for the causal inferences was unclear. OBJECTIVE: We aimed to investigate the causal link between life course adiposity and TMDs. METHODS: Mendelian randomization (MR) studies were performed using genetic instruments for birth weight (BW) (N = 261 932), childhood body mass index (BMI) (N = 39 620), childhood body size (N = 454 718), adult BMI (N = 99 998), body fat percentage (N = 454 633) and TMDs (N = 211 023). We assessed the overall effect of each life course adiposity factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct and indirect effects of childhood BMI on TMDs while accounting for BW and adult BMI, and vice versa. RESULTS: Univariable MR analyses revealed a causal effect of low childhood adiposity on an increased risk of TMDs (childhood BMI: IVW OR: 0.65, 95% CI: 0.54-0.78, p < .001; childhood body size: IVW OR: 0.56, 95% CI: 0.43-0.73, p < .001). No causal association existed between genetically predicted BW, adult BMI, or body fat percentage and TMDs. In the multivariable MR analyses, the effects of childhood BMI on TMDs occurrence remained significant and direct, even after adjusting for BW and adult BMI (multivariable IVW OR: 0.78, 95% CI: 0.61-0.99, p = .048). No pleiotropy and heterogeneity were detected (p > .05). CONCLUSION: Low childhood BMI might causally increase the risk of TMDs through a direct pathway.

Causal effects of educational attainment on temporomandibular disorders and the mediating pathways: A Mendelian randomization study.

BACKGROUND: As one of the most important indicators of socioeconomic status, educational attainment (EA) exhibits a strong association with temporomandibular disorders (TMDs). Despite this link, there is a lack of evidence regarding the causal role of EA in either facilitating or preventing TMDs. OBJECTIVE: This study aimed to investigate the causal effect of education on TMDs and explore potential mediating pathways. METHODS: Utilizing summary statistics from genome-wide association studies on years of schooling (N = 766 345) and TMDs (N = 211 023), we conducted Mendelian randomization (MR) to assess the overall effect of education. Additionally, a two-step MR approach was employed to evaluate 30 potential mediators and calculate the mediation proportions in the association. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and pleiotropy. RESULTS: Univariable MR analyses revealed a causal effect of lower EA on an increased risk of TMDs (OR: 0.53, 95% CI: 0.43-0.66, p < .001). Five out of 30 modifiable factors were identified as causal mediators in the associations of EA with TMDs, including feeling nervous (mediation proportion: 11.6%), feeling tense (10.2%), depression (9.6%), feeling worry (7.6%) and daily smoking (8.9%). Meanwhile, no pleiotropy was detected in the analyses (p > .05). CONCLUSION: Our findings supported that higher EA has a protective effect on the onset of TMDs, with partial mediation by psychological disorders and daily smoking. Interventions on these factors thus have the potential of substantially reducing the burden of TMDs attributed to low education.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study.

BACKGROUND: The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. RESULTS: Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (ß: 2.47, 95% CI: 0.93-4.01, p = 0.002), PhenoAA (ß: 3.00, 95% CI: 1.15-4.85, p = 0.001), and HannumAA (ß: 1.96, 95% CI: 0.58-3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). CONCLUSIONS: Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

Causal relationship between hypothyroidism and temporomandibular disorders: evidence from complementary genetic methods.

BACKGROUND: The role of thyroid health in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder, such as hypothyroidism or hyperthyroidism, is destructive in TMDs. This study aims to investigate the overall and specific causal effects of various thyroid conditions on TMDs. METHODS: Mendelian randomization (MR) studies were performed using genetic instruments for thyrotropin (TSH, N = 119,715), free thyroxine (fT4, N = 49,269), hypothyroidism (N = 410,141), hyperthyroidism (N = 460,499), and TMDs (N = 211,023). We assessed the overall effect of each thyroid factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct or indirect effects of hypothyroidism on TMDs whilst accounting for TSH, fT4 and hyperthyroidism, and vice versa. RESULTS: Univariable MR analyses revealed a causal effect of hypothyroidism on an increased risk of TMDs (IVW OR: 1.12, 95% CI: 1.05-1.20, p = 0.001). No significant association between genetically predicted hyperthyroidism, TSH, or fT4 and TMDs. In the multivariable MR analyses, the effects of hypothyroidism on TMDs occurrence remained significant even after adjSusting for TSH, fT4 and hyperthyroidism (multivariable IVW OR: 1.10, 95% CI: 1.03-1.17, p = 0.006). No pleiotropy and heterogeneity were detected in the analyses (p > 0.05). CONCLUSIONS: Hypothyroidism might causally increase the risk of TMDs through a direct pathway, highlighting the critical role of managing thyroid health in the prevention of TMDs. Clinicians should give heightened attention to patients with hypothyroidism when seeking medical advice for temporomandibular discomfort. However, caution is warranted due to the potential confounders, pleiotropy, and selection bias in the MR study.

Causal association between body mass index and temporomandibular disorders: a bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Observational studies have shown that body mass index (BMI) is highly correlated with the occurrence of temporomandibular disorders (TMDs). However, these studies failed to present a causal relationship. Thus, we aimed to performed a Mendelian randomization (MR) study to investigate causality between BMI and TMDs. METHODS: We performed a two-sample bidirectional MR analysis using large-scale genome-wide association studies (GWAS). Data were obtained from a large-scale BMI dataset (N = 322,154), TMDs dataset (N = 134,280). The causal effects were estimated with inverse-variance weighted (IVW) method, MR Egger, weighted median. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. RESULTS: In the forward MR analysis, a genetic prediction of low BMI was causally associated with a higher risk of TMDs (IVW OR: 0.575, 95% CI: 0.415-0.798, p: 0.001). Similar results were obtained using other complementary methods (MR Egger OR: 0.270, 95% CI: 0.104-0.698, p: 0.009; weighted median OR: 0.496, 95% CI: 0.298-0.826, p: 0.007). In the reverse MR results, TMDs was shown to have no significant effect on BMI (all p > 0.05). No pleiotropy and heterogeneity were detected in the bidirectional analysis (p > 0.05). CONCLUSION: A lower BMI might be causally associated with increased risk of TMDs, supporting the importance of weight control for the prevention of TMDs. Clinicians should pay more attention to the low-BMI patients among those seeking medical advice due to temporomandibular joint discomfort.