Cole A Weaver1, Steven F Miller2, Clarissa S G da Fontoura3, George L Wehby4, Brad A Amendt5, Nathan E Holton6, Veeratrishul Allareddy7, Thomas E Southard6, Lina M Moreno Uribe8. 1. Private practice, Cheyenne, Wyo. 2. 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. 3. The Iowa Institute for Oral and Craniofacial Research, College of Dentistry, University of Iowa, Iowa City, Iowa. 4. Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, Iowa. 5. Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa. 6. Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa. 7. Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, Iowa. 8. 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.
Abstract
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 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.
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 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: Steven D Marshall; Matthew Caspersen; Rachel R Hardinger; Robert G Franciscus; Steven A Aquilino; Thomas E Southard Journal: Am J Orthod Dentofacial Orthop Date: 2008-09 Impact factor: 2.650
Authors: Jennifer L Fish; Brian Villmoare; Katja Köbernick; Claudia Compagnucci; Olga Britanova; Victor Tarabykin; Michael J Depew Journal: Evol Dev Date: 2011 Nov-Dec Impact factor: 1.930
Authors: Lina M Moreno Uribe; Sara C Howe; Colleen Kummet; Kaci C Vela; Deborah V Dawson; Thomas E Southard Journal: Am J Orthod Dentofacial Orthop Date: 2014-03 Impact factor: 2.650
Authors: C S G da Fontoura; S F Miller; G L Wehby; B A Amendt; N E Holton; T E Southard; V Allareddy; L M Moreno Uribe Journal: J Dent Res Date: 2015-04-24 Impact factor: 6.116
Authors: Fan Liu; Fedde van der Lijn; Claudia Schurmann; Gu Zhu; M Mallar Chakravarty; Pirro G Hysi; Andreas Wollstein; Oscar Lao; Marleen de Bruijne; M Arfan Ikram; Aad van der Lugt; Fernando Rivadeneira; André G Uitterlinden; Albert Hofman; Wiro J Niessen; Georg Homuth; Greig de Zubicaray; Katie L McMahon; Paul M Thompson; Amro Daboul; Ralf Puls; Katrin Hegenscheid; Liisa Bevan; Zdenka Pausova; Sarah E Medland; Grant W Montgomery; Margaret J Wright; Carol Wicking; Stefan Boehringer; Timothy D Spector; Tomáš Paus; Nicholas G Martin; Reiner Biffar; Manfred Kayser Journal: PLoS Genet Date: 2012-09-13 Impact factor: 5.917