title: Genetic variants associated with development of TMD and its intermediate phenotypes: the genetic architecture of TMD in the OPPERA prospective cohort study.
abstract: Genetic risk factors are believed to combine with environmental exposures and contribute to the risk of developing temporomandibular disorder (TMD). In this prospective cohort study, 2,737 people without TMD were assessed for common genetic variation in 358 genes known to contribute to nociceptive pathways, inflammation, and affective distress. During a median follow-up period of 2.8 years, 260 people developed first-onset TMD. Hazard ratios were computed as measures of association between 2,924 single-nucleotide polymorphisms and TMD incidence. After correction for multiple testing, no single single-nucleotide polymorphism was significantly associated with risk of onset TMD. However, several single-nucleotide polymorphisms exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (.05, .1, or .2) for association with intermediate phenotypes shown to be predictive of TMD onset. Nonspecific orofacial symptoms were associated with voltage-gated sodium channel, type I, alpha subunit (SCN1A, rs6432860, P = 2.77 × 10(-5)) and angiotensin I-converting enzyme 2 (ACE2, rs1514280, P = 4.86 × 10(-5)); global psychological symptoms with prostaglandin-endoperoxide synthase 1 (PTGS1, rs3842803, P = 2.79 × 10(-6)); stress and negative affectivity with amyloid-β (A4) precursor protein (APP, rs466448, P = 4.29 × 10(-5)); and heat pain temporal summation with multiple PDZ domain protein (MPDZ, rs10809907, P = 3.05 × 10(-5)). The use of intermediate phenotypes for complex pain diseases revealed new genetic pathways influencing risk of TMD.
  
  
  CONCLUSIONS
  This article reports the findings of a large candidate gene association study of first-onset TMD and related intermediate phenotypes in the OPPERA Study. Although no genetic markers predicted TMD onset, several genetic risk factors for clinical, psychological, and sensory phenotypes associated with TMD onset were observed.
authors.affiliation: Regional Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Shad B
authors.initials: SB
authors.lastname: Smith
authors.forename: Ellen
authors.initials: E
authors.lastname: Mir
authors.forename: Eric
authors.initials: E
authors.lastname: Bair
authors.forename: Gary D
authors.initials: GD
authors.lastname: Slade
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
authors.forename: Roger B
authors.initials: RB
authors.lastname: Fillingim
authors.forename: Joel D
authors.initials: JD
authors.lastname: Greenspan
authors.forename: Richard
authors.initials: R
authors.lastname: Ohrbach
authors.forename: Charles
authors.initials: C
authors.lastname: Knott
authors.forename: Bruce
authors.initials: B
authors.lastname: Weir
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D013705:Temporomandibular Joint Disorders / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*
keywords: Temporomandibular disorder; chronic pain; genetic risk factors; incidence; intermediate phenotypes