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

Published

Journal Article

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). 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). 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). 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.

Full Text

Duke Authors

Cited Authors

  • Smith, SB; Parisien, M; Bair, E; Belfer, I; Chabot-Doré, A-J; Gris, P; Khoury, S; Tansley, S; Torosyan, Y; Zaykin, DV; Bernhardt, O; de Oliveira Serrano, P; Gracely, RH; Jain, D; Järvelin, M-R; 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

Published Date

  • March 2019

Published In

Volume / Issue

  • 160 / 3

Start / End Page

  • 579 - 591

PubMed ID

  • 30431558

Pubmed Central ID

  • 30431558

Electronic International Standard Serial Number (EISSN)

  • 1872-6623

Digital Object Identifier (DOI)

  • 10.1097/j.pain.0000000000001438

Language

  • eng

Conference Location

  • United States