Candidate Gene Analyses of Skeletal Variation in Malocclusion

Fontoura, Clarissa Souza Gomes da; Miller, Steven F.; Wehby, George L.; Amendt, Brad A.; Holton, Nathan E.; Southard, Thomas E.; Allareddy, Veerajalandhar; Uribe, Lina M. Moreno

doi:10.1177/0022034515581643

Cited by 104 publications

(113 citation statements)

References 39 publications

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“…12,13 In an effort to address some of these knowledge gaps, a recent genetic association study of 71 craniofacial genes/loci in white subjects with severe malocclusion used both categorical (skeletal Class II or Class III vs Class I) and quantitative skeletal malocclusion phenotypes derived from cephalometric tracings and geometric morphometrics methods, respectively. 14 This study showed that the risk for skeletal Class II relative to Class I was modulated by rare alleles in variants near FGFR2 and EDN1 , whereas Class III risk was modulated by variants in FGFR2, COL1A1 , and TBX5 . In addition, SNPs near SNAI3 were highly associated with skeletal variations ranging from severely concave to convex skeletal profiles and SNPs near TWIST1 were associated with variations ranging from a large to a short mandibular body.…”

mentioning

confidence: 73%

“…A sample of 300 untreated healthy subjects (average age, 29.9 years; age range, 12–68 years) seeking orthodontic treatment at the Department of Orthodontics of the University of Iowa was recruited and classified into skeletal Class I (n = 63), Class II (n = 154), or Class III (n = 83) according to criteria specified previously 14 and shown in Supplemental Figure 1. Of these, about 80% were white (n = 239), and the remaining subjects had other ancestries (Table I).…”

Section: Methodsmentioning

confidence: 99%

“…As described in our previous study, selection criteria for genes/loci were based on at least 1 of the following: (1) evidence of genetic association or linkage to malocclusion phenotypes in previous studies, (2) known expression patterns or biologic functions in the craniofacial complex, (3) known role in the etiology of craniofacial conditions with phenotypic spectra that include skeletal malocclusion, and (4) previous Genome Wide Association Analysis indicating association with craniofacial variation. 14 For SNP selection, haplotype blocks were reconstructed for all genes/loci, including 10-kb regions flanking intended intervals via Haploview, using genotypic data from a white population (HapMap CEU; HapMap release 27 based on February 2009 assembly, phase 2 and 3 versions). 32 A total of 224 tagging SNPs across 82 candidate genes and loci were selected.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, SNPs near SNAI3 were highly associated with skeletal variations ranging from severely concave to convex skeletal profiles and SNPs near TWIST1 were associated with variations ranging from a large to a short mandibular body. 14 Collectively, these findings suggest that malocclusion is a complex trait in both its phenotypic expression and its genetic etiology; therefore, continuing efforts to characterize phenotype-genotype correlations underlying the large variations of malocclusion phenotypes are warranted.…”

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confidence: 99%

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Candidate gene analyses of 3-dimensional dentoalveolar phenotypes in subjects with malocclusion

Weaver

Miller

Fontoura

et al. 2017

American Journal of Orthodontics and Dentofacial Orthopedics

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Introduction 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 TBX1 AJUBA, SNAI3 SATB2, 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.

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mentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Candidate gene analyses of 3-dimensional dentoalveolar phenotypes in subjects with malocclusion

Weaver

Miller

Fontoura

et al. 2017

American Journal of Orthodontics and Dentofacial Orthopedics

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“…This facilitates the examination of morphology in terms of shape variation without the confounding influence of size. In biology, shape variation is often used as a morphological proxy for genetic variation, and the interplay between genes and morphology has served as the basis for numerous studies of genotype vs. phenotype interactions in many different biological systems (Debat and David, 2001; Klingenberg et al, 2001; Workman et al, 2002; Klingenberg et al, 2004; Miller et al, 2014; da Fontoura et al, 2015). Typically, studies of morphological variation in bilaterally symmetric structures (such as the dental arches) address both aspects of symmetric and asymmetric shape variation.…”

Section: Introductionmentioning

confidence: 99%

Patterns of morphological integration in the dental arches of individuals with malocclusion

Miller

Vela²,

Levy

et al. 2016

American J Hum Biol

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Objectives In humans, there is a large range of variation in the form of the maxillary and mandibular dental arches. This variation can manifest as either prognathism or retrognathism in either or both arches, which can cause malocclusion and lead to abnormal masticatory function. This study aims to identify aspects of variation and morphological integration existing in the dental arches of individuals with different types of malocclusion. Methods Coordinate landmark data were collected along the gingival margins of 397 scanned dental casts and then analyzed using geometric morphometric techniques to explore arch form variation and patterns of morphological integration within each malocclusion type. Results Significant differences were identified between Class II forms (increased projection of upper arch relative to the lower arch) and Class III forms (lower arch projection beyond the upper arch) in symmetrical shape variation, including anteroposterior arch discrepancies and abnormal anterior arch divergence or convergence. Partial least squares analysis demonstrated that Class III dental arches have higher levels of covariance between upper and lower arches (RV=0.91) compared to the dental arches of Class II (RV=0.78) and Class I (RV=0.73. These high levels of covariance, however, are on the lower end of the overall range of possible masticatory blocks, indicating weaker than expected levels of integration. Conclusions This study provides evidence for patterns of variation in dental arch shape found in individuals with Class II and Class III malocclusions. Moreover, differences in integration found between malocclusion types have ramifications for how such pathologies should be studied and treated.

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Craniofacial Defects and Cleft Lip and Palate

Richman

Vora

2017

Encyclopedia of Life Sciences

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Serious malformations of the face present at birth are due to disturbances of embryonic development. Formation of the face begins during the fifth week post conception, and by 7 weeks, the lip is completely fused and continuous. The secondary palate forms between 7 and 11 weeks and is influenced by the growth of the surrounding head. Early disruption of lip and palate morphogenesis gives rise to severe orofacial clefts, whereas later disturbances cause microforms of clefting. Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is linked to polymorphisms in multiple genes and influences from the environment. In contrast, syndromic facial anomalies are attributed to defined changes in the genome and are accompanied by deficiencies in several organ systems. Key Concepts The face is susceptible to malformations due to the complex 4D nature of embryonic morphogenesis. Multiple prominences need to come together and fuse at precisely the right time during development in order for lip and palate fusion to occur. The genes that cause syndromes with craniofacial phenotypes overlap with the genes that contribute to nonsyndromic abnormalities such as typical cleft lip with or without cleft palate. Abnormal jaw relationships, especially mandibular prognathism, are partially genetically determined. Novel genes that increase risk of being born with NSCL/P have been identified with Genome Wide Association Studies and targeted sequencing. Midline clefts have a different etiology and appearance than non‐syndromic cleft lip. Midline clefts are part of the midline deficiencies in holoprosencephaly.

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Candidate Gene Analyses of Skeletal Variation in Malocclusion

Cited by 104 publications

References 39 publications

Candidate gene analyses of 3-dimensional dentoalveolar phenotypes in subjects with malocclusion

Candidate gene analyses of 3-dimensional dentoalveolar phenotypes in subjects with malocclusion

Patterns of morphological integration in the dental arches of individuals with malocclusion

Craniofacial Defects and Cleft Lip and Palate

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