Family-based GWAS for dental class I malocclusion and clefts.

BACKGROUND: Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts. METHODS: Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion. RESULTS: In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate. CONCLUSIONS: These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.

O fenótipo radiográfico da maxila na maloclusão Classe III / The radiographic phenotype of the maxilla in Class III malocclusion

A maloclusão Classe III apresenta diversidade fenotípica que se expressa por retrusão esquelética da maxila, protrusão esquelética da mandíbula ou combinação de ambas. A literatura evidencia que a maxila apresenta alteração, em 49,6% dos casos da maloclusão Classe III. Objetiva-se investigar e reconhecer características fenotípicas da maxila nesta maloclusão, utilizadandose duas casuísticas: a primeira, integrada por 195 indivíduos, oriundos de 8 famílias, com alta prevalência das características craniofaciais da Classe III, (86 afetados e 109 não afetados). A segunda, constituída por 47 indivíduos, sendo 28 com maloclusão Classe III de Angle e 19 com maloclusão Classe I. Os projetos foram submetidos e aprovados no Comitê de Ética em Pesquisa junto ao Hospital Universitário Clementino Fraga Filho. O mesmo operador (L.T.V) realizou a análise de todas as radiografias e tomografias. Medidas lineares e angulares foram avaliadas, para identificar as dimensões da maxila. Os resultados foram analisados estatisticamente: na amostra 2D por Shapiro-Wilk, após comprovada distribuição não normal, o teste selecionado foi teste de Mann-Whitney para comparação intergrupos e entre gêneros. Enquanto a amostra 3D foi submetida ao teste Kolmogorov-Smirnov e mediante a distribuição normal dos dados foi realizado teste t e Correlação de Pearson. Os resultados evidenciaram significante envolvimento na anatomia dos processos alveolares, mostrando-se distintos entre indivíduos Classe III e Classe I, quanto à altura, largura e espessura, assim como alteração do fenótipo nos indivíduos afetados em comparação aos não afetados, em algumas dimensões das estruturas e na localização espacial, com ênfase na deficiência anteroposterior maxilar. Concluiuse que existem variações anatômicas em diferentes partes da maxila, entre os grupos, entretanto a localização espacial da mesma, no sentido anteroposterior, foi determinante na configuração fenotípica da maloclusão Classe III esquelética. (AU)

Class III malocclusion presents phenotypic diversity that is expressed by skeletal retrusion of the maxilla, skeletal protrusion of the mandible or a combination of both. The literature shows that the maxilla presents some kind of alterations, in 49.6% of Class III malocclusion cases. The aim of this study was to recognize phenotypic characteristics of the maxilla in subjects with Class III expression, two samples were used: the first, comprising 195 subjects, from 8 families, with high prevalence of the Class III craniofacial characteristics (86 affected and 109 unaffected). The second, consisting of 47 subjects, 19 with Class I malocclusion and 28 with Angle Class III malocclusion. This study was approved by Comitê de Ética em Pesquisa in Hospital Universitário Clementino Fraga Filho. The same operator (L.T.V) performed the analysis of all radiographs and conebeam computed tomography. Linear and angular measurements were evaluated to identify the dimensions of the maxilla. The results were analyzed statistically: in the 2D sample, Shapiro-Wilk and Kolmogorov-Smirnov, after proven non-normal distribution the selected test was the Mann-Whitney test for intergroup and gender comparison. While a 3D sample was submitted to Shapiro-Wilk and KolmogorovSmirnov, provided the normal data distribution, the t test and Pearson's correlation were performed. The results showed a significant involvement in the anatomy of the alveolar processes, showing a difference between Class III and Class I individuals, as for height, width and thickness, as well as alteration of the phenotype in the affected individuals compared to the unaffected ones, in some dimensions of the structures and in the spatial location, with emphasis on the anteroposterior deficiency. It was concluded that there are anatomical variations in different parts of the maxilla, between the groups, however its spatial location, in the anteroposterior direction, characterized the phenotypic configuration of skeletal Class III malocclusion. (AU)

Candidate Gene Analyses of Skeletal Variation in Malocclusion.

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.

Analysis of genetic polymorphisms in skeletal Class I crowding.

INTRODUCTION: Dental crowding is a problem for both adolescents and adults in modern society. The purpose of this research was to identify single nucleotide polymorphisms (SNPs) responsible for crowding in subjects with skeletal Class I relationships. METHODS: The case subjects consisted of healthy Chinese people living in Hong Kong with skeletal Class I relationships and at least 5 mm of crowding in either arch. The control subjects met the same requirements but lacked crowding or spacing. SNP genotyping was performed on the MassARRAY platform. The chi-square test was used to compare genotype and allele type distributions between the case and the control groups. Logistic regression was used to calculate odds ratios with 95% confidence intervals, and the effects of age and sex for each SNP. Analyses of linkage disequilibrium and haplotype associations between SNPs were performed with software. RESULTS: Five SNPs were found to be significantly different in genotype or allele type distributions. SNP rs372024 was significantly associated with crowding (P = 0.004). Two SNPs, rs3764746 and rs3795170, on the EDA gene were found to be associated marginally. SNPs rs1005464 and rs15705 also exhibited marginal association with crowding. The effects of associated SNPs remained significant after adjustments for age and sex factors. CONCLUSIONS: This study suggests an association for the genes EDA and XEDAR in dental crowding in the Hong Kong Chinese population.

Mandibular lateral incisor-canine transposition in monozygotic twins.

Mandibular tooth transposition, involving the right lateral incisor and canine, is described in monozygotic twin girls. This report provides evidence suggesting that genetic factors influence the development of mandibular lateral incisor-canine (Mn.I2.C) transposition. Interceptive orthodontic treatment for children with this rare occlusal abnormality should be considered.