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


Painful temporomandibular disorders (TMD) is the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. While 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 GWAS 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 three distinct loci that were significant in combined or sex-segregated analyses. A single nucleotide polymorphism (SNP) on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio [OR]=2.9, 95% CI: 2.02-4.27, P=2.2x10). This association was nominally replicated in a meta-analysis of seven independent orofacial pain cohorts including 160,194 participants (OR=1.16, 95% CI: 1.0-1.35, P = 2.3x10). Functional analysis in human dorsal root ganglia (DRG) and blood indicated this variant is an expression quantitative trait locus (eQTL), with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43x10). 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.Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.






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Publication Info

Smith, Shad B, Marc Parisien, Eric Bair, Inna Belfer, Anne-Julie Chabot-Doré, Pavel Gris, Samar Khoury, Shannon Tansley, et al. (2018). Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain. 10.1097/j.pain.0000000000001438 Retrieved from

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Shad Benjamin Smith

Associate Professor in Anesthesiology

Dr. Shad Smith is an assistant professor in the Department of Anesthesiology and holds a faculty position in the Center for Translational Pain Medicine (CTPM). Dr. Smith also has an adjunct appointment at the University of North Carolina at Chapel Hill, as part of the Center for Pain Research and Innovation (CPRI). He earned his bachelor’s degree in psychology with minors in chemistry and zoology from Brigham Young University, before moving on to graduate school.

In 2006, he graduated with a doctorate in psychology with an emphasis in behavioral neuroscience. Following his time at McGill, Dr. Smith accepted a post-doctoral fellowship in the CPRI at the UNC School of Dentistry. He received a Ruth L. Kirschstein National Research Service Award in 2008 to study the role of alpha adrenergic mechanisms in chronic orofacial pain. He joined the faculty at UNC as a research assistant professor in 2011. Dr. Smith has also served since 2007 as a research consultant, and since 2010 as the Director of Bioinformatics, for Algynomics, Inc., a Chapel Hill-based biotech firm spun off from research activities within the UNC School of Dentistry.

Dr. Smith joined the faculty at Duke University in 2016, where he continues his work with genetics of pain disorders. The primary focus of his research career has been the search for genetic variation that contributes to greater pain sensitivity and increased risk for chronic pain disease. He has worked for over a decade with genomic techniques, including both quantitative trait locus (QTL) mapping in the mouse and genetic association in human pain cohorts, investigating a number of pain-related diseases and phenotypes. Dr. Smith has published over 40 journal articles and book chapters, and presented his work at several international meetings. His work with projects such as the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study has resulted in a number of novel genes being recognized as genetic risk factors for pain.


Andrea Gail Nackley

Associate Professor in Anesthesiology

Pain is a multidimensional sensory and emotional experience that is important for our survival, but once pain becomes chronic it is no longer beneficial and, instead, becomes a disorder in and of itself. Chronic pain remains one of our nation’s most significant healthcare problems due to a limited understanding of the underlying genetic and environmental factors. There are three main objectives of our lab’s research in this area: 

  1. To determine the factors that put some people, but not others, at risk for maladaptive chronic pain conditions. To achieve this objective, we study genetic, biological, and environmental factors associated with the initial onset of pain as well as its severity and duration. In addition, we are beginning to study factors associated with patient-centered outcomes, which may have the power to predict optimal management strategies for different individuals.
  2. To elucidate the mechanism(s) whereby genetic, biological, and environmental factors drive chronic pain. To achieve this objective, we integrate molecular genetics, animal models, and clinical epidemiologic measures in order to reveal pathogenic processes that are unique to as well as common across a particular condition or individual(s). This line of inquiry will provide novel targets for the development of individualized therapeutics for the management of chronic pain.
  3. To improve pharmacologic management of pain. To achieve this objective, we conduct pre-clinical studies to test the efficacy of new compounds and to optimize the efficacy of existing compounds in patient-relevant animal models.

Luda Diatchenko

Adjunct Professor in the Department of Anesthesiology

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