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 LaniadoCathy 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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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
Issue number3
StatePublished - Mar 1 2019


  • 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


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