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; 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 D. Greenspan; Richard Ohrbach; Gary D. Slade; William Maixner; Luda Diatchenko

doi:10.1097/j.pain.0000000000001438

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

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 D. Greenspan, Richard Ohrbach, Gary D. Slade, William Maixner, Luda Diatchenko

Oral Diagnostic Sciences Administration

Duke University
McGill University
University of North Carolina at Chapel Hill
National Institutes of Health
United States Food and Drug Administration
University of Greifswald
Universidade Estadual de Campinas
University of Washington
Imperial College London
University of Oulu
Brunel University London
University of Illinois at Chicago
Albert Einstein College of Medicine
University of Florida
University of Eastern Finland
Harvard University
Brigham and Women’s Hospital
University of Maryland, Baltimore

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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 language	English
Pages (from-to)	579-591
Number of pages	13
Journal	Pain
Volume	160
Issue number	3
DOIs	https://doi.org/10.1097/j.pain.0000000000001438
State	Published - Mar 1 2019

Keywords

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

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10.1097/j.pain.0000000000001438

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Smith, S. B., Parisien, M., Bair, E., Belfer, I., Chabot-Doré, A. J., Gris, P., Khoury, S., Tansley, S., Torosyan, Y., Zaykin, D. V., Bernhardt, O., De Oliveira Serrano, P., Gracely, R. H., Jain, D., Järvelin, M. R., Kaste, L. M., Kerr, K. F., Kocher, T., Lähdesmäki, R., ... 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

@article{82f1182474484116802a341d3d8a055c,

title = "Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males",

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.",

keywords = "Bioinformatics, Chronic pain, Expression quantitative trait locus, Genome-wide association study, Meta-analysis, Temporomandibular joint disease",

author = "Smith, \{Shad B.\} and Marc Parisien and Eric Bair and Inna Belfer and Chabot-Dor{\'e}, \{Anne Julie\} and Pavel Gris and Samar Khoury and Shannon Tansley and Yelizaveta Torosyan and Zaykin, \{Dmitri V.\} and Olaf Bernhardt and \{De Oliveira Serrano\}, Priscila and Gracely, \{Richard H.\} and Deepti Jain and J{\"a}rvelin, \{Marjo Riitta\} and Kaste, \{Linda M.\} and Kerr, \{Kathleen F.\} and Thomas Kocher and Raija L{\"a}hdesm{\"a}ki and Nadia Laniado and Laurie, \{Cathy C.\} and Laurie, \{Cecelia A.\} and Minna M{\"a}nnikk{\"o} and Meloto, \{Carolina B.\} and Nackley, \{Andrea G.\} and Nelson, \{Sarah C.\} and Paula Pesonen and Ribeiro-Dasilva, \{Margarete C.\} and Rizzatti-Barbosa, \{Celia M.\} and Sanders, \{Anne E.\} and Christian Schwahn and Kirsi Sipil{\"a} and Tamar Sofer and Alexander Teumer and Mogil, \{Jeffrey S.\} and Fillingim, \{Roger B.\} and Greenspan, \{Joel D.\} and Richard Ohrbach and Slade, \{Gary D.\} and William Maixner and Luda Diatchenko",

note = "Publisher Copyright: {\textcopyright} 2018 International Association for the Study of Pain.",

year = "2019",

month = mar,

day = "1",

doi = "10.1097/j.pain.0000000000001438",

language = "English",

volume = "160",

pages = "579--591",

journal = "Pain",

issn = "0304-3959",

publisher = "Lippincott Williams and Wilkins",

number = "3",

}

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

TY - JOUR

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 D.

AU - Ohrbach, Richard

AU - Slade, Gary D.

AU - Maixner, William

AU - Diatchenko, Luda

PY - 2019/3/1

Y1 - 2019/3/1

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

UR - https://www.scopus.com/pages/publications/85061610268

U2 - 10.1097/j.pain.0000000000001438

DO - 10.1097/j.pain.0000000000001438

M3 - Article

C2 - 30431558

AN - SCOPUS:85061610268

SN - 0304-3959

VL - 160

SP - 579

EP - 591

JO - Pain

JF - Pain

IS - 3

ER -

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

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Keywords

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