A two-sample Mendelian randomization study on the association between temporomandibular disorder and insomnia

doi:10.7518/hxkq.2025.2024255

Abstract

Abstract:

Objective This study aimed to investigate the association between temporomandibular disorder (TMD) and insomnia using a two-sample Mendelian randomization (MR) approach. Methods Bidirectional MR analyses of two samples, TMD (n=377 277) and insomnia (n=375 359), were performed using genome-wide association study statistics published in the FinnGen database. Instrumental variables were first screened, and then inverse variance weighting (IVW) and MR-Egger were used as the main-effect assessment methods. Weighted median, weighted mode, and Simple mode served as supplementary methods. We used IVW and MR-Egger to test for heterogeneity, as well as MR-Egger intercepts to assess the single nucleotide polymorphism (SNP) potential level of multiplicity effects. Sensitivity analyses were conducted based on leave-one-out to identify potentially influential SNPs. All analyses were conducted using R (V.4.2.2) by using the two-sample MR R package and were considered statistically significant when P<0.05. Results MR analysis showed the presence of TMD on insomnia (OR=1.089, 95%CI: 1.017-1.166, P=0.014). Meanwhile, no effect of insomnia on TMD (OR=0.996, 95%CI: 0.964-1.029, P=0.816) was found. The sensitivity-analysis showed that no heterogeneity existed (P>0.05), and the presence of horizontal pleiotropy was not detected (P>0.05). Leave-one-out sensitivity analysis showed no single SNP, which may affect the causal relation. All findings indicated that the causal relationship between TMD and insomnia was not significantly affected by any individual SNP and that IV did not bias the results. Conclusion Results of MR analyses showed that TMD is a risk factor for insomnia, whereas insomnia is not a risk factor for TMD.

Key words: temporomandibular disorder, insomnia, Mendelian randomization, genome-wide association study, risk factors

CLC Number:

R782.6

Yuan Wei, Cheng Yiming, Cui Yunyi, Gao Duoduo. A two-sample Mendelian randomization study on the association between temporomandibular disorder and insomnia[J]. West China Journal of Stomatology, 2025, 43(3): 354-361.

Figures/Tables 5

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References 57

1	Resende CM, Alves AC, Coelho LT, et al. Quality of life and general health in patients with temporomandibular disorders[J]. Braz Oral Res, 2013, 27(2): 116-121.
2	Valesan LF, Da-Cas CD, Réus JC, et al. Prevalence of temporomandibular joint disorders: a systematic review and meta-analysis[J]. Clin Oral Investig, 2021, 25(2): 441-453.
3	Chisnoiu AM, Picos AM, Popa S, et al. Factors involved in the etiology of temporomandibular disorders—A literature review[J]. Clujul Med, 2015, 88(4): 473-478.
4	Sójka A, Huber J, Hędzelek W, et al. Relations between the results of complex clinical and neurophysiological examinations in patients with temporomandibular disorders symptoms[J]. Cranio, 2018, 36(1): 44-52.
5	Rener-Sitar K, Celebić A, Mehulić K, et al. Factors rela-ted to oral health related quality of life in TMD patients[J]. Coll Antropol, 2013, 37(2): 407-413.
6	Bair MJ, Wu J, Damush TM, et al. Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients[J]. Psychosom Med, 2008, 70(8): 890-897.
7	Sójka A, Stelcer B, Roy M, et al. Is there a relationship between psychological factors and TMD[J]. Brain Behav, 2019, 9(9): e01360.
8	Dibello V, Panza F, Mori G, et al. Temporomandibular disorders as a risk factor for suicidal behavior: a systematic review[J]. J Pers Med, 2022, 12(11): 1782.
9	Andrade L, Caraveo-Anduaga JJ, Berglund P, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemio-logy (ICPE) Surveys[J]. Int J Methods Psychiatr Res, 2003, 12(1): 3-21.
10	Andreescu C, Lee S. Anxiety disorders in the elderly[J]. Adv Exp Med Biol, 2020, 1191: 561-576.
11	Rehm J, Shield KD. Global burden of disease and the impact of mental and addictive disorders[J]. Curr Psychiatry Rep, 2019, 21(2): 10.
12	Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications[J]. Dialogues Clin Neurosci, 2008, 10(4): 473-481.
13	Manber R, Chambers AS. Insomnia and depression: a multifaceted interplay[J]. Curr Psychiatry Rep, 2009, 11(6): 437-442.
14	Staner L. Comorbidity of insomnia and depression[J]. Sleep Med Rev, 2010, 14(1): 35-46.
15	Lowe H, Haddock G, Mulligan LD, et al. Does exercise improve sleep for adults with insomnia? A systematic review with quality appraisal[J]. Clin Psychol Rev, 2019, 68: 1-12.
16	Bolge SC, Doan JF, Kannan H, et al. Association of insomnia with quality of life, work productivity, and activity impairment[J]. Qual Life Res, 2009, 18(4): 415-422.
17	Smith MT, Wickwire EM, Grace EG, et al. Sleep disorders and their association with laboratory pain sensitivity in temporomandibular joint disorder[J]. Sleep, 2009, 32(6): 779-790.
18	Haack M, Simpson N, Sethna N, et al. Sleep deficien-cy and chronic pain: potential underlying mechanisms and clinical implications[J]. Neuropsychopharmacology, 2020, 45(1): 205-216.
19	Herrero Babiloni A, De Koninck BP, Beetz G, et al. Sleep and pain: recent insights, mechanisms, and future directions in the investigation of this relationship[J]. J Neural Transm (Vienna), 2020, 127(4): 647-660.
20	Finan PH, Goodin BR, Smith MT. The association of sleep and pain: an update and a path forward[J]. J Pain, 2013, 14(12): 1539-1552.
21	Smith MT, Quartana PJ, Okonkwo RM, et al. Mechanisms by which sleep disturbance contributes to osteoarthritis pain: a conceptual model[J]. Curr Pain Headache Rep, 2009, 13(6): 447-454.
22	Sánchez Romero EA, Martínez-Pozas O, García-Gonzá- lez M, et al. Association between sleep disorders and sleep quality in patients with temporomandibular joint osteoarthritis: a systematic review[J]. Biomedicines, 2022, 10(9): 2143.
23	Burgess S, Labrecque JA. Mendelian randomization with a binary exposure variable: interpretation and presentation of causal estimates[J]. Eur J Epidemiol, 2018, 33(10): 947-952.
24	Botelho J, Machado V, Mendes JJ, et al. Causal association between periodontitis and Parkinson’s disease: a bidirectional mendelian randomization study[J]. Genes (Basel), 2021, 12(5): 772.
25	Ding M, Zhang Z, Chen Z, et al. Association between periodontitis and breast cancer: two-sample Mendelian randomization study[J]. Clin Oral Investig, 2023, 27(6): 2843-2849.
26	Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study[J]. BMC Med, 2022, 20(1): 443.
27	Chen Y, Shen J, Wu Y, et al. Tea consumption and risk of lower respiratory tract infections: a two-sample mendelian randomization study[J]. Eur J Nutr, 2023, 62(1): 385-393.
28	Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies[J]. Int J Epidemiol, 2011, 40(3): 755-764.
29	Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations[J]. Bioinformatics, 2019, 35(22): 4851-4853.
30	Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods[J]. Stat Med, 2016, 35(11): 1880-1906.
31	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525.
32	Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome[J]. Elife, 2018, 7: e34408.
33	Yang M, Yu H, Xu K, et al. No evidence of a genetic causal relationship between ankylosing spondylitis and iron homeostasis: a two-sample Mendelian randomization study[J]. Front Nutr, 2023, 10: 1047640.
34	Lee YH. Causal association between smoking behavior and the decreased risk of osteoarthritis: a Mendelian randomization[J]. Z Rheumatol, 2019, 78(5): 461-466.
35	Finan PH, Garland EL. The role of positive affect in pain and its treatment[J]. Clin J Pain, 2015, 31(2): 177-187.
36	Zautra AJ, Johnson LM, Davis MC. Positive affect as a source of resilience for women in chronic pain[J]. J Consult Clin Psychol, 2005, 73(2): 212-220.
37	Litt MD, Shafer D, Napolitano C. Momentary mood and coping processes in TMD pain[J]. Health Psychol, 2004, 23(4): 354-362.
38	Sturgeon JA, Arewasikporn A, Okun MA, et al. The psychosocial context of financial stress: implications for inflammation and psychological health[J]. Psychosom Med, 2016, 78(2): 134-143.
39	Stellar JE, John-Henderson N, Anderson CL, et al. Positive affect and markers of inflammation: discrete positive emotions predict lower levels of inflammatory cytokines[J]. Emotion, 2015, 15(2): 129-133.
40	Steptoe A, O’Donnell K, Badrick E, et al. Neuroendocrine and inflammatory factors associated with positive affect in healthy men and women: the WhitehallⅡstudy[J]. Am J Epidemiol, 2008, 167(1): 96-102.
41	Prather AA, Marsland AL, Muldoon MF, et al. Positi-ve affective style covaries with stimulated IL-6 and IL-10 production in a middle-aged community sample[J]. Brain Behav Immun, 2007, 21(8): 1033-1037.
42	Slavish DC, Jones DR, Smyth JM, et al. Positive and negative affect and salivary markers of inflammation among young adults[J]. Int J Behav Med, 2020, 27(3): 282-293.
43	Rener-Sitar K, John MT, Pusalavidyasagar SS, et al. Sleep quality in temporomandibular disorder cases[J]. Sleep Med, 2016, 25: 105-112.
44	Irwin MR. Why sleep is important for health: a psychoneuroimmunology perspective[J]. Annu Rev Psychol, 2015, 66: 143-172.
45	Chinthakanan S, Laosuwan K, Boonyawong P, et al. Reduced heart rate variability and increased saliva cortisol in patients with TMD[J]. Arch Oral Biol, 2018, 90: 125-129.
46	Duarte J, Pinto-Gouveia J. Positive affect and parasympathetic activity: evidence for a quadratic relationship between feeling safe and content and heart rate variability[J]. Psychiatry Res, 2017, 257: 284-289.
47	Fredrickson BL, Mancuso RA, Branigan C, et al. The un-doing effect of positive emotions[J]. Motiv Emot, 2000, 24(4): 237-258.
48	Waldburger JM, Firestein GS. Regulation of peripheral inflammation by the central nervous system[J]. Curr Rheumatol Rep, 2010, 12(5): 370-378.
49	Hunt CA, Mun CJ, Owens MA, et al. Sleep, positive affect, and circulating interleukin-6 in women with tempo-romandibular joint disorder[J]. Psychosom Med, 2022, 84(3): 383-392.
50	Farré-Guasch E, Aliberas JT, Spada NF, et al. The role of inflammatory markers in temporomandibular myalgia: a systematic review[J]. Jpn Dent Sci Rev, 2023, 59: 281-288.
51	Akkaoui MA, Palagini L, Geoffroy PA. Sleep immune cross talk and insomnia[J]. Adv Exp Med Biol, 2023, 1411: 263-273.
52	Buenaver LF, Quartana PJ, Grace EG, et al. Evidence for indirect effects of pain catastrophizing on clinical pain among myofascial temporomandibular disorder participants: the mediating role of sleep disturbance[J]. Pain, 2012, 153(6): 1159-1166.
53	Lautenbacher S. Pain, sleeping problems and their many relatives[J]. Pain, 2012, 153(6): 1138.
54	Sommer I, Lavigne G, Ettlin DA. Review of self-repor-ted instruments that measure sleep dysfunction in patients suffering from temporomandibular disorders and/or orofacial pain[J]. Sleep Med, 2015, 16(1): 27-38.
55	Cardinali DP, Srinivasan V, Brzezinski A, et al. Melatonin and its analogs in insomnia and depression[J]. J Pineal Res, 2012, 52(4): 365-375.
56	Vidor LP, Torres IL, Custódio de Souza IC, et al. Analgesic and sedative effects of melatonin in temporoman-dibular disorders: a double-blind, randomized, parallel-group, placebo-controlled study[J]. J Pain Symptom Ma-nage, 2013, 46(3): 422-432.
57	Kim SJ, Park SM, Cho HJ, et al. The relationship between primary sleep disorders and temporomandibular disorders: an 8-year nationwide cohort study in south Korea[J]. Int J Gen Med, 2021, 14: 7121-7131.

结局	暴露	方法	OR值	95%CI	P值
TMD	失眠	IVW	0.996	0.964~1.029	0.816
		MR-Egger法	0.977	0.915~1.044	0.498
		加权中位数估计	1.021	0.975~1.069	0.374
		加权模式	1.020	0.905~1.149	0.744
		简单模式	1.018	0.910~1.139	0.755
失眠	TMD	IVW	1.089	1.017~1.166	0.014
		MR-Egger法	1.099	0.956~1.263	0.189
		加权中位数估计	1.074	0.974~1.184	0.152
		加权模式	1.031	0.795~1.337	0.818
		简单模式	1.016	0.756~1.366	0.916

暴露	结局	异质性				MR-Egger水平多效性
暴露	结局	Q值	df	I2	P值	PD截距	SE	P值
失眠	TMD	87.087	82	5.841%	0.330	0.003	0.005	0.517
TMD	失眠	97.313	100	2.761%	0.557	-0.001	0.007	0.888

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