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

Smith, Shad B.a; Parisien, Marcb; Bair, Ericc,d; Belfer, Innae; Chabot-Doré, Anne-Julieb; Gris, Pavelb; Khoury, Samarb; Tansley, Shannonb,f; Torosyan, Yelizavetag; Zaykin, Dmitri V.h; Bernhardt, Olafi; de Oliveira Serrano, Priscilaj; Gracely, Richard H.c; Jain, Deeptik; Järvelin, Marjo-Riittal,m,n,o; Kaste, Linda M.p; Kerr, Kathleen F.k; Kocher, Thomasi; Lähdesmäki, Raijaq,r; Laniado, Nadias; Laurie, Cathy C.k; Laurie, Cecelia A.k; Männikkö, Minnam,t; Meloto, Carolina B.b; Nackley, Andrea G.a; Nelson, Sarah C.k; Pesonen, Paulau; Ribeiro-Dasilva, Margarete C.v; Rizzatti-Barbosa, Celia M.j; Sanders, Anne E.c,w; Schwahn, Christianx; Sipilä, Kirsiy,z,q,r; Sofer, Tamaraa,bb; Teumer, Alexandercc; Mogil, Jeffrey S.b,f; Fillingim, Roger B.dd; Greenspan, Joel D.ee; Ohrbach, Richardff; Slade, Gary D.c,w,gg; Maixner, Williama; Diatchenko, Ludab,*

doi: 10.1097/j.pain.0000000000001438
Research Paper
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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.

A polymorphic locus associated with a protective effect against painful temporomandibular disorder in males regulates the expression of the muscle RAS oncogene homolog (MRAS) gene.

aDepartment of Anesthesiology, Center for Translational Pain Medicine, Duke University, Durham, NC, United States

bAlan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada

cCenter for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

dDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

eNational Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD, United States

fDepartment of Psychology, McGill University, Montreal, QC, Canada

gDivision of Epidemiology, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, United States

hBiostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, United States

iDepartment of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany

jDepartment of Prosthesis and Periodontology, Piracicaba Dental School, State University of Campinas, Piracicaba, São Paulo, Brazil

kDepartment of Biostatistics, University of Washington, Seattle, WA, United States

lDepartment of Epidemiology and Biostatistics, Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom

mCenter for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

nBiocenter Oulu, University of Oulu, and Unit of Primary Care, Oulu University Hospital, Oulu, Finland

oDepartment of Life Sciences, College of Health and Life Sciences, Brunel University London, United Kingdom

pDepartment of Pediatric Dentistry, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States

qResearch Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland

rMedical Research Center Oulu, Oulu University Hospital, Oulu, Finland

sDepartment of Dentistry, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY, United States

tFaculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland

uNorthern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Finland

vDivision of Prosthodontics, Restorative Dental Science Department, College of Dentistry, University of Florida, Gainesville, FL, United States

wDepartment of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

xDepartment of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, Greifswald, Germany

yInstitute of Dentistry, University of Eastern Finland, Kuopio, Finland

zOral and Maxillofacial Department, Kuopio University Hospital, Kuopio, Finland

aaDepartment of Medicine, Harvard Medical School, Boston, MA, United States

bbDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, United States

ccInstitute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

ddDepartment of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL, United States

eeDepartment of Neural and Pain Sciences, Brotman Facial Pain Clinic, University of Maryland, School of Dentistry, Baltimore, MD, United States

ffDepartment of Oral Diagnostic Services, University at Buffalo, Buffalo, NY, United States

ggDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Corresponding author. Address: Alan Edwards Centre for Research on Pain, Genome Building, Room 2201, 740 Dr. Penfield Ave, Montreal, QC H3A 0G1, Canada. Tel.: 514-398-2878; fax: 514-398-8900. E-mail address: luda.diatchenko@mcgill.ca (L. Diatchenko).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received July 24, 2018

Accepted October 25, 2018

© 2019 International Association for the Study of Pain
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