Facial Pain With Localized and Widespread Manifestations: Separate Pathways of Vulnerability

Pain. 2013 Nov;154(11):2335-43. doi: 10.1016/j.pain.2013.07.009. Epub 2013 Jul 16.


Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2925 single nucleotide polymorphisms (SNPs) and 2 subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P=0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P=0.0014). A risk index representing combined effects of 6 SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio 2.7, P=1.3 E-09), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio 1.6, P=0.014). A risk index representing combined effects of 8 SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P=1.9 E-08), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background.

Keywords: Case-control study; Human genetics; Serotonergic receptor; Temporomandibular disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Cohort Studies
  • DNA / genetics
  • Facial Pain / genetics*
  • Facial Pain / physiopathology*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Antigen, T-Cell / physiology
  • Risk
  • Serotonin / physiology
  • Sex Characteristics
  • Signal Transduction / genetics*
  • Signal Transduction / physiology*
  • Temporomandibular Joint Disorders / genetics
  • Temporomandibular Joint Disorders / physiopathology
  • Young Adult


  • Receptors, Antigen, T-Cell
  • Serotonin
  • DNA