Smith SB, et al. - In order to assess the underlying molecular mechanisms of painful temporomandibular disorders (TMDs), which are the leading cause of chronic orofacial pain, researchers undertook 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. They identified 3 distinct loci that were significant in combined or sex-segregated analyses using logistic models adjusted for sex, age, enrollment site, and race. In males, they observed a significant association of a single-nucleotide polymorphism on chromosome 3 (rs13078961) with TMD. This variant was identified to be an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene in functional analysis in human dorsal root ganglia and blood. As per genetic and behavioral evidence, they identified a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. As this effect is male-specific, it may explain the lower rates of painful TMD in men.