Is there a causal association between temporomandibular disorders and COVID-19 risk? A genetic instrumental variables analysis.

The coronavirus disease 2019 (COVID-19) and temporomandibular joint disorders (TMD) as the two major diseases are being focused by the public in modern societies. Previous epidemiological studies have shown increase in TMD prevalence during COVID-19 pandemic era. This study was aimed to verify the causal association between two sides using bidirectional mendelian randomization (MR) analysis. It explored whether COVID-19 could cause TMD or TMD influenced the COVID-19 susceptibility. Furthermore it was aimed to eliminate the reverse relationship and other confounders, and an attempt was made to provide etiologic evidence. Single-nucleotide polymorphisms (SNPs) related to three COVID-19 phenotypes (p < 5 × 10^-8) were selected from the genome-wide association study (GWAS) data collected through COVID-19 host genetics initiative (HGI). SNPs related to TMD (p < 5 × 10^-6) were collected from GWAS data in UK Biobank (UKB). Inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression estimated the causal effect between two sides in this study. Furthermore, four sensitivity analyses (MR-PRESSO, Cochran's Q test, MR-Egger intercept test, and leave-one-out test) were used to confirm the robust results. TMD-related GWAS in FinnGen repeated the MR to validate the results. COVID-19 was not affected by TMD. The reversed MR suggested no significant causal effect of COVID-19 on TMD. Sensitivity analyses showed no gene pleiotropy and had robust results in this MR. Nonetheless, the MR statistical power was <80%, which suggested insufficient sample size of COVID-19 and TMD. This study based on current evidence depicted that COVID-19 had no impact on TMD, and TMD did not increase the susceptibility of severe acute respiratory syndrome coronavirus-2. During COVID-19 pandemic, excessive psychological stress caused by COVID-19 might act as a mediator between the two diseases. The relationship between the two sides needs verification by more external studies in the future.