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Candidate Gene Analyses of Skeletal Variation in Malocclusion.

ABSTRACT: This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 single-nucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation among patients with malocclusion, while FGFR2, EDN1, TBX5, and COL1A1 are associated with type of skeletal malocclusion.

SUBMITTER: da Fontoura CS

PROVIDER: S-EPMC4530344 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Candidate Gene Analyses of Skeletal Variation in Malocclusion.

da Fontoura C S G CS Miller S F SF Wehby G L GL Amendt B A BA Holton N E NE Southard T E TE Allareddy V V Moreno Uribe L M LM

Journal of dental research 20150424 7

This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. ...[more]

PMID: 25910506

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Project description:IntroductionGenetic 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.MethodsPretreatment 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.ResultsPrincipal 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.ConclusionsSpecific genetic pathways associated with 3-dimensional dentoalveolar phenotypic variation in malocclusions were identified.

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Candidate Gene Analyses of Skeletal Variation in Malocclusion.

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Candidate Gene Analyses of Skeletal Variation in Malocclusion.

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