title: Candidate gene analyses of 3-dimensional dentoalveolar phenotypes in subjects with malocclusion.
abstract: BACKGROUND
  Genetic studies of malocclusion etiology have identified 4 deleterious mutations in genes DUSP6,ARHGAP21, FGF23, and ADAMTS1 in familial Class III cases. Although these variants may have large impacts on Class III phenotypic expression, their low frequency (<1%) makes them unlikely to explain most malocclusions. Thus, much of the genetic variation underlying the dentofacial phenotypic variation associated with malocclusion remains unknown. In this study, we evaluated associations between common genetic variations in craniofacial candidate genes and 3-dimensional dentoalveolar phenotypes in patients with malocclusion.
  
  
  METHODS
  Pretreatment dental casts or cone-beam computed tomographic images from 300 healthy subjects were digitized with 48 landmarks. The 3-dimensional coordinate data were submitted to a geometric morphometric approach along with principal component analysis to generate continuous phenotypes including symmetric and asymmetric components of dentoalveolar shape variation, fluctuating asymmetry, and size. The subjects were genotyped for 222 single-nucleotide polymorphisms in 82 genes/loci, and phenotpye-genotype associations were tested via multivariate linear regression.
  
  
  RESULTS
  Principal component analysis of symmetric variation identified 4 components that explained 68% of the total variance and depicted anteroposterior, vertical, and transverse dentoalveolar discrepancies. Suggestive associations (P < 0.05) were identified with PITX2, SNAI3, 11q22.2-q22.3, 4p16.1, ISL1, and FGF8. Principal component analysis for asymmetric variations identified 4 components that explained 51% of the total variations and captured left-to-right discrepancies resulting in midline deviations, unilateral crossbites, and ectopic eruptions. Suggestive associations were found with TBX1AJUBA, SNAI3SATB2, TP63, and 1p22.1. Fluctuating asymmetry was associated with BMP3 and LATS1. Associations for SATB2 and BMP3 with asymmetric variations remained significant after the Bonferroni correction (P <0.00022). Suggestive associations were found for centroid size, a proxy for dentoalveolar size variation with 4p16.1 and SNAI1.
  
  
  CONCLUSIONS
  Specific genetic pathways associated with 3-dimensional dentoalveolar phenotypic variation in malocclusions were identified.
authors.affiliation: Private practice, Cheyenne, Wyo.
authors.forename: Cole A
authors.initials: CA
authors.lastname: Weaver
authors.affiliation: Department of Anatomy, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Ill; Department of Dental Medicine, College of Dental Medicine-Illinois, Midwestern University, Downers Grove, Ill.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Miller
authors.affiliation: The Iowa Institute for Oral and Craniofacial Research, College of Dentistry, University of Iowa, Iowa City, Iowa.
authors.forename: Clarissa S G
authors.initials: CS
authors.lastname: da Fontoura
authors.affiliation: Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, Iowa.
authors.forename: George L
authors.initials: GL
authors.lastname: Wehby
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Amendt
authors.affiliation: Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Holton
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa.
authors.forename: Veeratrishul
authors.initials: V
authors.lastname: Allareddy
authors.affiliation: Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Southard
authors.affiliation: The Iowa Institute for Oral and Craniofacial Research, College of Dentistry, University of Iowa, Iowa City, Iowa; Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa. Electronic address: lina-moreno@uiowa.edu.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Moreno Uribe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D059925:Anatomic Landmarks; D002648:Child; D054893:Cone-Beam Computed Tomography; D005260:Female; D000089703:Fibroblast Growth Factor-23; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008310:Malocclusion / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D025341:Principal Component Analysis; D015203:Reproducibility of Results