Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males

Shad B. Smith, Marc Parisien, Eric Bair, Inna Belfer, Anne Julie Chabot-Doré, Pavel Gris, Samar Khoury, Shannon Tansley, Yelizaveta Torosyan, Dmitri V. Zaykin, Olaf Bernhardt, Priscila De Oliveira Serrano, Richard H. Gracely, Deepti Jain, Marjo Riitta Järvelin, Linda M. Kaste, Kathleen F. Kerr, Thomas Kocher, Raija Lähdesmäki, Nadia Laniado & 21 others Cathy C. Laurie, Cecelia A. Laurie, Minna Männikkö, Carolina B. Meloto, Andrea G. Nackley, Sarah C. Nelson, Paula Pesonen, Margarete C. Ribeiro-Dasilva, Celia M. Rizzatti-Barbosa, Anne E. Sanders, Christian Schwahn, Kirsi Sipilä, Tamar Sofer, Alexander Teumer, Jeffrey S. Mogil, Roger B. Fillingim, Joel Daniel Greenspan, Richard Ohrbach, Gary D. Slade, William Maixner, Luda Diatchenko

Research output: Contribution to journalArticle

Abstract

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10 -8 ). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10 -2 ). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10 -5 ). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

Original languageEnglish (US)
Pages (from-to)579-591
Number of pages13
JournalPain
Volume160
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

Fingerprint

Temporomandibular Joint Disorders
Genome
Facial Pain
Chronic Pain
Odds Ratio
Confidence Intervals
Behavioral Genetics
Twin Studies
Chromosomes, Human, Pair 3
Quantitative Trait Loci
Genome-Wide Association Study
Genetic Models
Hyperalgesia
Spinal Ganglia
Oncogenes
Single Nucleotide Polymorphism
Meta-Analysis
Logistic Models
Alleles
Pain

Keywords

  • Bioinformatics
  • Chronic pain
  • Expression quantitative trait locus
  • Genome-wide association study
  • Meta-analysis
  • Temporomandibular joint disease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Smith, S. B., Parisien, M., Bair, E., Belfer, I., Chabot-Doré, A. J., Gris, P., ... Diatchenko, L. (2019). Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain, 160(3), 579-591. https://doi.org/10.1097/j.pain.0000000000001438

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. / Smith, Shad B.; Parisien, Marc; Bair, Eric; Belfer, Inna; Chabot-Doré, Anne Julie; Gris, Pavel; Khoury, Samar; Tansley, Shannon; Torosyan, Yelizaveta; Zaykin, Dmitri V.; Bernhardt, Olaf; De Oliveira Serrano, Priscila; Gracely, Richard H.; Jain, Deepti; Järvelin, Marjo Riitta; Kaste, Linda M.; Kerr, Kathleen F.; Kocher, Thomas; Lähdesmäki, Raija; Laniado, Nadia; Laurie, Cathy C.; Laurie, Cecelia A.; Männikkö, Minna; Meloto, Carolina B.; Nackley, Andrea G.; Nelson, Sarah C.; Pesonen, Paula; Ribeiro-Dasilva, Margarete C.; Rizzatti-Barbosa, Celia M.; Sanders, Anne E.; Schwahn, Christian; Sipilä, Kirsi; Sofer, Tamar; Teumer, Alexander; Mogil, Jeffrey S.; Fillingim, Roger B.; Greenspan, Joel Daniel; Ohrbach, Richard; Slade, Gary D.; Maixner, William; Diatchenko, Luda.

In: Pain, Vol. 160, No. 3, 01.03.2019, p. 579-591.

Research output: Contribution to journalArticle

Smith, SB, Parisien, M, Bair, E, Belfer, I, Chabot-Doré, AJ, Gris, P, Khoury, S, Tansley, S, Torosyan, Y, Zaykin, DV, Bernhardt, O, De Oliveira Serrano, P, Gracely, RH, Jain, D, Järvelin, MR, Kaste, LM, Kerr, KF, Kocher, T, Lähdesmäki, R, Laniado, N, Laurie, CC, Laurie, CA, Männikkö, M, Meloto, CB, Nackley, AG, Nelson, SC, Pesonen, P, Ribeiro-Dasilva, MC, Rizzatti-Barbosa, CM, Sanders, AE, Schwahn, C, Sipilä, K, Sofer, T, Teumer, A, Mogil, JS, Fillingim, RB, Greenspan, JD, Ohrbach, R, Slade, GD, Maixner, W & Diatchenko, L 2019, 'Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males', Pain, vol. 160, no. 3, pp. 579-591. https://doi.org/10.1097/j.pain.0000000000001438
Smith SB, Parisien M, Bair E, Belfer I, Chabot-Doré AJ, Gris P et al. Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain. 2019 Mar 1;160(3):579-591. https://doi.org/10.1097/j.pain.0000000000001438
Smith, Shad B. ; Parisien, Marc ; Bair, Eric ; Belfer, Inna ; Chabot-Doré, Anne Julie ; Gris, Pavel ; Khoury, Samar ; Tansley, Shannon ; Torosyan, Yelizaveta ; Zaykin, Dmitri V. ; Bernhardt, Olaf ; De Oliveira Serrano, Priscila ; Gracely, Richard H. ; Jain, Deepti ; Järvelin, Marjo Riitta ; Kaste, Linda M. ; Kerr, Kathleen F. ; Kocher, Thomas ; Lähdesmäki, Raija ; Laniado, Nadia ; Laurie, Cathy C. ; Laurie, Cecelia A. ; Männikkö, Minna ; Meloto, Carolina B. ; Nackley, Andrea G. ; Nelson, Sarah C. ; Pesonen, Paula ; Ribeiro-Dasilva, Margarete C. ; Rizzatti-Barbosa, Celia M. ; Sanders, Anne E. ; Schwahn, Christian ; Sipilä, Kirsi ; Sofer, Tamar ; Teumer, Alexander ; Mogil, Jeffrey S. ; Fillingim, Roger B. ; Greenspan, Joel Daniel ; Ohrbach, Richard ; Slade, Gary D. ; Maixner, William ; Diatchenko, Luda. / Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. In: Pain. 2019 ; Vol. 160, No. 3. pp. 579-591.
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T1 - Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males

AU - Smith, Shad B.

AU - Parisien, Marc

AU - Bair, Eric

AU - Belfer, Inna

AU - Chabot-Doré, Anne Julie

AU - Gris, Pavel

AU - Khoury, Samar

AU - Tansley, Shannon

AU - Torosyan, Yelizaveta

AU - Zaykin, Dmitri V.

AU - Bernhardt, Olaf

AU - De Oliveira Serrano, Priscila

AU - Gracely, Richard H.

AU - Jain, Deepti

AU - Järvelin, Marjo Riitta

AU - Kaste, Linda M.

AU - Kerr, Kathleen F.

AU - Kocher, Thomas

AU - Lähdesmäki, Raija

AU - Laniado, Nadia

AU - Laurie, Cathy C.

AU - Laurie, Cecelia A.

AU - Männikkö, Minna

AU - Meloto, Carolina B.

AU - Nackley, Andrea G.

AU - Nelson, Sarah C.

AU - Pesonen, Paula

AU - Ribeiro-Dasilva, Margarete C.

AU - Rizzatti-Barbosa, Celia M.

AU - Sanders, Anne E.

AU - Schwahn, Christian

AU - Sipilä, Kirsi

AU - Sofer, Tamar

AU - Teumer, Alexander

AU - Mogil, Jeffrey S.

AU - Fillingim, Roger B.

AU - Greenspan, Joel Daniel

AU - Ohrbach, Richard

AU - Slade, Gary D.

AU - Maixner, William

AU - Diatchenko, Luda

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N2 - Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10 -8 ). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10 -2 ). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10 -5 ). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

AB - Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10 -8 ). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10 -2 ). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10 -5 ). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

KW - Bioinformatics

KW - Chronic pain

KW - Expression quantitative trait locus

KW - Genome-wide association study

KW - Meta-analysis

KW - Temporomandibular joint disease

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