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.

COVID-19; Temporomandibular joint disorders; Mendelian randomization analysis; Psychosocial factors; Biostatistics

[1] Special Expert Group for Control of the Epidemic of Novel Coronavirus Pneumonia of the Chinese Preventive Medicine Association. An update on the epidemiological characteristics of novel coronavirus pneumonia (COVID-19). Zhonghua Liu Xing Bing Xue Za Zhi. 2020; 41: 139–144. (In Chinese)

[2] Zhao N, Zhou N, Fan H, Ding J, Xu X, Dong X, et al. Mutations and phylogenetic analyses of SARS-CoV-2 among imported COVID-19 from abroad in Nanjing, China. Frontiers in Microbiology. 2022; 13: 851323.

[3] Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al.; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. The New England Journal of Medicine. 2020; 382: 1708–1720.

[4] Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, Behavior, and Immunity. 2020; 87: 34–39.

[5] He Z, Akinwunmi B, Ming WK. Editorial: psychosocial, behavioral, and clinical implications for public mental health during the COVID-19 pandemic. Frontiers in Psychiatry. 2023; 14: 1274588.

[6] Pan A, Wu Y, Chen X, Yu W, Wu X, Chen L, et al. A qualitative study of psychological stress among China’s frontline nurses fighting COVID-19. Archives of Medical Science. 2022; 18: 1407–1412.

[7] National Institute of Dental and Craniofacial Research. Facial pain. 2018. Available at: https://www.nidcr.nih.gov/research/data-statistics/facial-pain (Accessed: 28 April 2024).

[8] LeResche L. Epidemiology of temporomandibular disorders: implications for the investigation of etiologic factors. Critical Reviews in Oral Biology & Medicine. 1997; 8: 291–305.

[9] Shahidi S, Salehi P, Abedi P, Dehbozorgi M, Hamedani S, Berahman N. Comparison of the bony changes of TMJ in patients with and without TMD complaints using CBCT. Journal of Dentistry. 2018; 19: 142-149.

[10] Benoliel R. Classifying head, face and oral pain. Cephalalgia. 2017; 37: 1315–1316.

[11] Li DTS, Leung YY. Temporomandibular disorders: current concepts and controversies in diagnosis and management. Diagnostics. 2021; 11: 459.

[12] Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet J, et al. Diagnostic criteria for temporomandibular disorders (DC/TMD) for clinical and research applications: recommendations of the international RDC/TMD consortium network and orofacial pain special interest group. Journal of Oral & Facial Pain and Headache. 2014; 28: 6–27.

[13] List T, Jensen RH. Temporomandibular disorders: old ideas and new concepts. Cephalalgia. 2017; 37: 692–704.

[14] Xiang Y, Song J, Liang Y, Sun J, Zheng Z. Causal relationship between psychiatric traits and temporomandibular disorders: a bidirectional two-sample Mendelian randomization study. Clinical Oral Investigations. 2023; 27: 7513–7521.

[15] Dos Santos EA, Peinado BRR, Frazão DR, Né YGS, Fagundes NCF, Magno MB, et al. Association between temporomandibular disorders and anxiety: a systematic review. Frontiers in Psychiatry. 2022; 13: 990430.

[16] Łazarz-Półkoszek MJ, Orczykowska M, Gala A, Pihut M. Impact of the COVID-19 pandemic on patients’ anxiety levels related to dental appointments in Poland. Dental and Medical Problems. 2023; 60: 367–373.

[17] Winocur-Arias O, Winocur E, Shalev-Antsel T, Reiter S, Levartovsky S, Emodi-Perlman A, et al. Painful temporomandibular disorders, bruxism and oral parafunctions before and during the COVID-19 pandemic era: a sex comparison among dental patients. Journal of Clinical Medicine. 2022; 11: 589.

[18] Ghadirian H, Khami MR, Tabatabaei SN, Mirhashemi AH, Bahrami R. COVID-19 vaccination and psychological status of Iranian dental students. Frontiers in Public Health. 2022; 10: 946408.

[19] Scelza G, Amato A, Rongo R, Nucci L, D’Ambrosio F, Martina S. Changes in COVID-19 perception and in TMD prevalence after 1 year of pandemic in Italy. European Journal of Dentistry. 2023; 17: 771–776.

[20] Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA. 2017; 318: 1925–1926.

[21] Boef AGC, Dekkers OM, le Cessie S. Mendelian randomization studies: a review of the approaches used and the quality of reporting. International Journal of Epidemiology. 2015; 44: 496–511.

[22] COVID-19 Host Genetics Initiative. The COVID-19 host genetics initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. European Journal of Human Genetics. 2020; 28: 715–718.

[23] Jiang L, Zheng Z, Fang H, Yang J. A generalized linear mixed model association tool for biobank-scale data. Nature Genetics. 2021; 53: 1616–1621.

[24] Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K, Donner KM, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023; 613: 508–518.

[25] Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. International Journal of Epidemiology. 2011; 40: 755–764.

[26] Papadimitriou N, Dimou N, Tsilidis KK, Banbury B, Martin RM, Lewis SJ, et al. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis. Nature Communications. 2020; 11: 597.

[27] Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genetic Epidemiology. 2013; 37: 658–665.

[28] Xiao G, He Q, Liu L, Zhang T, Zhou M, Li X, et al. Causality of genetically determined metabolites on anxiety disorders: a two-sample Mendelian randomization study. Journal of Translational Medicine. 2022; 20: 475.

[29] Lawlor DA, Wade KH, Borges MC, Palmer T, Hartwig FP, Hemani G, et al. A Mendelian randomization dictionary: useful definitions and descriptions for undertaking, understanding and interpreting Mendelian randomization studies. To be published in OSF Preprints. 2019. [Preprint].

[30] Verbanck M, Chen C, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nature Genetics. 2018; 50: 693–698.

[31] Shalev-Antsel T, Winocur-Arias O, Friedman-Rubin P, Naim G, Keren L, Eli I, et al. The continuous adverse impact of COVID-19 on temporomandibular disorders and bruxism: comparison of pre- during- and post-pandemic time periods. BMC Oral Health. 2023; 23: 716.

[32] Metin A, Erbiçer ES, Şen S, Çetinkaya A. Gender and COVID-19 related fear and anxiety: a meta-analysis. Journal of Affective Disorders. 2022; 310: 384–395.

[33] Yap AU, Park JW, Lei J, Liu C, Kim SH, Lee BM, et al. The influence of the COVID-19 pandemic, sex, and age on temporomandibular disorders subtypes in East Asian patients: a retrospective observational study. BMC Oral Health. 2023; 23: 248.

[34] Minervini G, Franco R, Marrapodi MM, Mehta V, Fiorillo L, Badnjević A, et al. The association between COVID-19 related anxiety, stress, depression, temporomandibular disorders, and headaches from childhood to adulthood: a systematic review. Brain Sciences. 2023; 13: 481.

[35] Zuhour M, Ismayilzade M, Dadacı M, Ince B. The impact of wearing a face mask during the COVID-19 pandemic on temporomandibular joint: a radiological and questionnaire assessment. Indian Journal of Plastic Surgery. 2022; 55: 58–65.

[36] Pihut M, Orczykowska M, Gala A. Risk factors for the development of temporomandibular disorders related to the work environment—a literature review and own experience. Folia Medica Cracoviensia. 2022; 62: 43–49.

[37] Burgess S, Davies NM, Thompson SG. Bias due to participant overlap in two‐sample Mendelian randomization. Genetic Epidemiology. 2016; 40: 597–608.

[38] Zou L, Guo H, Berzuini C. Overlapping-sample Mendelian randomisation with multiple exposures: a Bayesian approach. BMC Medical Research Methodology. 2020; 20: 295.

[39] Kanten P, Gümüştekin G, Kanten S. Exploring the role of A, B, C and D personality types on individuals work-related behaviors and health problems: a theoretical model. International Journal of Business and Management Invention. 2017; 6: 29–37.

[40] Gębska M, Dalewski B, Pałka Ł, Kołodziej Ł, Sobolewska E. Type D personality and stomatognathic system disorders in physiotherapy students during the COVID-19 pandemic. Journal of Clinical Medicine. 2021; 10: 4892.

[41] Zach GA, Andreasen K. Evaluation of the psychological profiles of patients with signs and symptoms of temporomandibular disorders. The Journal of Prosthetic Dentistry. 1991; 66: 810–812.

[42] Ohrbach R, Dworkin SF. The evolution of TMD diagnosis. Journal of Dental Research. 2016; 95: 1093–1101.

[43] Emodi-Perlman A, Eli I, Smardz J, Uziel N, Wieckiewicz G, Gilon E, et al. Temporomandibular disorders and bruxism outbreak as a possible factor of orofacial pain worsening during the COVID-19 pandemic-concomitant research in two countries. Journal of Clinical Medicine. 2020; 9: 3250.

[44] saki M, shadmanpour M, Zarif Najafi H. Are individuals with orofacial pain more prone to psychological distress during the COVID-19 pandemic? Dental and Medical Problems. 2021; 58: 17–25.

[45] Alona E, Ilana E. One year into the COVID-19 pandemic—temporomandibular disorders and bruxism: what we have learned and what we can do to improve our manner of treatment. Dental and Medical Problems. 2021; 58: 215–218.

[46] Papadimitriou G. The “Biopsychosocial Model”: 40 years of application in psychiatry. Psychiatriki. 2017; 28: 107–110.