Influence of COL2A1-G1405S polymorphism on mandibular skeletal malocclusions: A genetic association study and in silico analysis.

OBJECTIVE: The current study aimed to assess the association between collagen type II alpha 1 chain (COL2A1) single nucleotide polymorphism (SNP: rs2070739; C>T; G1405S) and mandibular skeletal malocclusions in the population of Mazandaran (North Iran). DESIGN: During 13 months, 102 control samples, 81 samples with skeletal Class III malocclusion contributed by mandibular prognathism and 82 samples with skeletal Class II malocclusion contributed by mandibular retrognathism were screened. Cephalometric analysis was performed to determine the type of abnormalities. COL2A1-G1405S genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The HOPE tool was used to investigate the effect of COL2A1-G1405S on the three-dimensional structure of protein. RESULTS: Results showed that there is no significant correlation between genotypes and alleles related to COL2A1-G1405S and mandibular prognathism (CT genotype: p-value= 0.210; T allele: p-value= 0.222). On the other hand, an association was observed between COL2A1-G1405S and mandibular retrognathism (CT genotype: p-value= 0.008; T allele: p-value= 0.011). The outputs of the HOPE tool also showed that COL2A1-G1405S can disrupt the NC1 domain of the protein. CONCLUSIONS: Here, we provide evidence that COL2A1-G1405S polymorphism may have positive correlation with the risk of skeletal Class II malocclusion contributed by mandibular retrognathism in the population of Mazandaran. Given that the COL2A1-G1405S occurs in NC1 domain, it is possible that this domain plays an important role in signaling pathways related to ossification. So, we suggest that the study of COL2A1 SNPs can help researchers understand the significant role of this collagen in mandibular skeletal malocclusions.

Orofacial Cleft and Mandibular Prognathism-Human Genetics and Animal Models.

Many complex molecular interactions are involved in the process of craniofacial development. Consequently, the network is sensitive to genetic mutations that may result in congenital malformations of varying severity. The most common birth anomalies within the head and neck are orofacial clefts (OFCs) and prognathism. Orofacial clefts are disorders with a range of phenotypes such as the cleft of the lip with or without cleft palate and isolated form of cleft palate with unilateral and bilateral variations. They may occur as an isolated abnormality (nonsyndromic-NSCLP) or coexist with syndromic disorders. Another cause of malformations, prognathism or skeletal class III malocclusion, is characterized by the disproportionate overgrowth of the mandible with or without the hypoplasia of maxilla. Both syndromes may be caused by the presence of environmental factors, but the majority of them are hereditary. Several mutations are linked to those phenotypes. In this review, we summarize the current knowledge regarding the genetics of those phenotypes and describe genotype-phenotype correlations. We then present the animal models used to study these defects.

Genetic effect of single nucleotide polymorphisms in growth hormone receptor gene on the risk of non-syndromic mandibular prognathism in the Korean population.

OBJECTIVES: To evaluate the association of three single-nucleotide polymorphisms (SNPs) of growth hormone receptor (GHR) gene with mandibular prognathism (MP) and relationships between mandibular morphology and GHR gene SNPs in the Korean population. MATERIALS AND METHODS: A total of 325 subjects were divided into two groups based on sagittal maxillomandibular relationship by the lateral cephalography: the MP and control groups. From the SNPs in the GHR gene, three SNPs (rs6180, rs6182 and rs6184) were selected. SNP genotyping was performed using direct sequencing. The craniofacial measurements of lateral cephalography were analysed. RESULTS: We found a lack of association between GHR and MP. However, in the analysis according to the values of cephalometric measurements, rs6180 was significantly associated with ANB, SNB, effective mandibular length and SNMP in females. Additionally, rs6182 and rs6184 were significantly associated with ramal height in males. CONCLUSION: Growth hormone receptor SNPs may affect not only the sagittal development of mandible but also the vertical development of ramal height, and GHR SNPs may gender-differently influence mandibular morphology. This finding supports that the GHR might be susceptible on mandibular morphogenesis in the Korean population.

Targeted sequencing of NOTCH signaling pathway genes and association analysis of variants correlated with mandibular prognathism.

INTRODUCTION: The purpose of this study was to systematically identify variants in NOTCH signaling pathway genes that correlate with mandibular prognathism (MP) in the general Chinese population. METHODS: Targeted sequencing of NOTCH signaling pathway genes was conducted in 199 MP individuals and 197 class I malocclusion control individuals. The associations of common and rare variants with MP, cephalometric parameters, and continuous cephalometric phenotypes were analyzed by principal component (PC) analysis. The associations between rare variants and MP were tested for each gene. RESULTS: Six SNPs, including rs415929, rs520688, and rs423023 in an exonic region of NOTCH4; rs1044006 in an exonic region of NOTCH3; rs1051415 in an exonic region of JAG1; and rs75236173 in the 3'-untranslated region (3'-UTR) of NUMB were associated with MP (P < 0.05). One common variant, rs1051415, in an exonic region of JAG1 was significantly related to PC1 (P  = 3.608 × 10- 4), which explained 24.3% of the overall phenotypic variation observed and corresponded to the sagittal mandibular position towards the maxilla, ranging from a posterior positioned mandible to an anterior positioned mandible. Additionally, 41 other variants were associated with PC1-5 (P  <  0.05). With respect to rare variant analysis, variants within the EP300, NCOR2, and PSEN2 gene showed an association with MP (t   < 0 .05). CONCLUSIONS: An association between NOTCH signaling pathway genes and MP has been identified.

Relationship of the rs10850110 and rs11611277 polymorphisms of the MYO1H gene with non-syndromic mandibular prognathism in the Iranian population.

BACKGROUND: The myosin 1H (MYO1H) gene, located on chromosome 12, encodes the unconventional MYO1H protein, which is involved in the intracellular movement and morphology of chondrocytes, and plays a vital role in the prognathism or retrognathism of the mandible. OBJECTIVES: The objective of this study was to assess the relationship between the polymorphisms of the MYO1H gene and mandibular prognathism in the Iranian population. MATERIAL AND METHODS: The current project evaluated 64 patients with mandibular prognathism requiring orthognathic surgery and 60 controls with skeletal class I occlusion. Genome amplification was performed using specific primer pairs to assess the rs10850110 and rs11611277 polymorphisms of the MYO1H gene through the polymerase chain reaction (PCR). The restriction fragment length polymorphism (RFLP) technique was used to detect single-nucleotide polymorphisms. The data was analyzed using the χ2 test. RESULTS: The patient and control groups were not significantly different in terms of age or gender (p > 0.05). In all, 3.1% of patients and 6.7% of controls had the rs10850110 polymorphism (p = 0.680), and 1.6% of patients and 5% of controls had the rs11611277 polymorphism (p = 0.602). CONCLUSIONS: No significant correlation was noted between the rs10850110 and rs11611277 polymorphisms of the MYO1H gene and mandibular prognathism in the Iranian population. However, the lower frequency of these polymorphisms in the patient group suggests a possible association with mandibular retrognathism, which needs to be investigated with a larger sample size.

Three novel genes tied to mandibular prognathism in eastern Mediterranean families.

INTRODUCTION: Mandibular prognathism (MP) is subject to major polygenic influence and segregates within families in autosomal dominance with variable expressivity and incomplete penetrance. We aimed to identify the inheritance pattern and genes and loci involved in the development of MP in Mediterranean families and to evaluate the dentoskeletal characteristics of affected individuals. METHODS: Fifty-one eastern Mediterranean families with individuals affected by MP were identified. Data and biospecimens were collected from 14 of the families, including clinical examination, lateral cephalography (on subjects with Class III malocclusion), and 5 mL blood drawn from consenting affected and nonaffected relatives. Next-generation sequencing (NGS) was performed on 8 families (7 Lebanese, 1 Lebanese/Syrian), including large numbers of affected individuals over many generations and severe conditions, with the use of whole-exome sequencing. RESULTS: Most pedigrees suggested autosomal-dominant inheritance with an equal number of affected male and female individuals. Affected individuals had macrognathic and prognathic mandibles with dentoalveolar compensation. Genetic screening did not correspond with previously reported MP-linked genes, but yielded 3 novel genes (C1orf167, NBPF8, NBPF9) on chromosome 1 potentially responsible for mandibular development and macrognathism. CONCLUSIONS: In this first genetic study with the use of NGS on the largest reported number of families with MP, novel genes (C1orf167, NBPF8, NBPF9) were associated with familial MP in the eastern Mediterranean population.

Whole-exome sequencing in a Japanese pedigree implicates a rare non-synonymous single-nucleotide variant in BEST3 as a candidate for mandibular prognathism.

Mandibular prognathism is a phenotype of facial deformity seen in populations around the world, but with higher incidence among East Asian populations. Five genome-wide nonparametric linkage analyses and a genome-wide association study to identify susceptibility loci of the phenotype have shown inconsistent results. To explore variants related to mandibular prognathism, we undertook whole-exome sequencing in a Japanese pedigree. The pedigree was ascertained as mandibular prognathism. The pedigree comprised 15 individuals from 4 generations. Four affected individuals across 2 generations and 5 unaffected individuals were chosen for whole-exome sequencing. Five non-synonymous single-nucleotide variants (SNVs) of UBASH3B, OR6M1, OR8D4, OR8B4, and BEST3 genes were detected in all 4 affected individuals, but in none of the 5 unaffected individuals. A non-synonymous SNV of the BEST3 gene, Chr12(GRCh37):g.70048878G>T, NM_032735.2:c.1816C>A, p.(L606I), was identified as rare missense variant. BEST3 is located on chromosome 12q15 and encodes bestrophin 3 from the bestrophin family of anion channels. The 4 other non-synonymous SNVs of UBASH3B, OR6M1, OR8D4, and OR8B4 were not considered plausible candidates for mandibular prognathism. Our whole-exome sequencing implicates a rare non-synonymous SNV of BEST3 as a candidate for mandibular prognathism in the Japanese pedigree.

Identification and Functional Studies of MYO1H for Mandibular Prognathism.

Mandibular prognathism (MP) is regarded as a craniofacial deformity resulting from the combined effects of environmental and genetic factors, while the genetically predetermined component is considered to play an important role to develop MP. Although linkage and association studies for MP have identified multiple strongly associated regions and genes, the causal genes and variants responsible for the deformity remain largely undetermined. To address this, we performed targeted sequencing of 396 genes selected from previous studies as well as genes and pathways related with craniofacial development as primary candidates in 199 MP cases and 197 controls and carried out a series of statistical and functional analyses. A nonsynonymous common variant of MYO1H rs3825393, C>T, p.Pro1001Leu, was identified to be significantly associated with MP. During zebrafish embryologic development, expression of MYO1H orthologous genes were detected at mandibular jaw. Furthermore, jaw cartilage defects were observed in zebrafish knockdown models. Collectively, these data demonstrate that MYO1H is required for proper jaw growth and contributes to MP pathogenesis, expanding our knowledge of the genetic basis of MP.

Genetic Factors Involved in Mandibular Prognathism.

Mandibular prognathism is defined as an abnormal forward projection of the mandible beyond the standard relation to the cranial base and it is usually categorized as both a skeletal Class III pattern and Angle Class III malocclusion. The etiology of mandibular prognathism is still uncertain, with various genetic, epigenetic, and environmental factors possibly involved. However, many reports on its coexistence in both twins and segregation in families suggest the importance of genetic influences. A multifactorial and polygenic background with a threshold for expression or an autosomal dominant mode with incomplete penetrance and variable expressivity are the most probable inheritance patterns. Linkage analyses have, thus far, shown the statistical significance of such loci as 1p22.1, 1p22.3, 1p32.2, 1p36, 3q26.2, 4p16.1, 6q25, 11q22, 12pter-p12.3, 12q13.13, 12q23, 12q24.11, 14q24.3 to 31.2, and 19p13.2. The following appear among candidate genes: MATN1, EPB41, growth hormone receptor, COL2A1, COL1A1, MYO1H, DUSP6, ARHGAP21, ADAMTS1, FGF23, FGFR2, TBX5, ALPL, HSPG2, EVC, EVC2, the HoxC gene cluster, insulin-like growth factor 1, PLXNA2, SSX2IP, TGFB3, LTBP2, MMP13/CLG3, KRT7, and FBN3. On the other hand, MYH1, MYH2, MYH3, MYH7, MYH8, FOXO3, NFATC1, PTGS2, KAT6B, HDAC4, and RUNX2 expression is suspected to be involved in the epigenetic regulations behind the mandibular prognathism phenotype.

Targeted sequencing in FGF/FGFR genes and association analysis of variants for mandibular prognathism.

To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism (MP) in the general Chinese population systematically.Targeted sequencing of the FGF/FGFR genes was conducted in 176 MP individuals and 155 class I malocclusion controls. The associations of common and rare variants with MP as a categorical phenotype and also continuous malocclusion phenotypes generated by principal component (PC) analysis were analyzed.One common variant, rs372127537, located in the 3'-untranslated region of FGF7 gene, was significantly related to PC1 (P  =  4.22 × 10), which explained 23.23% of the overall phenotypic variation observed and corresponded to vertical discrepancies ranging from short anterior face height to long anterior face height, after Bonferroni correction. Also, 15 other variants were associated with PC1-4, although not significant after multiple corrections (P < .05). We also identified 3 variants: rs13317 in FGFR1, rs149242678 in FGF20, and rs79176051 FGF12 associated with MP (P < .05). With respect to rare variant analysis, variants within the FGF12 gene showed significant association with MP (P  =  .001).Association between FGF/FGFR signaling pathway and MP has been identified. We found a previously unreported SNP in FGF7 significantly related to increased facial height. Also, rare variants within the FGF12 were associated with MP. Our results provide new clues for genetic mechanisms of MP and shed light on strategies for evaluating rare variants that underlie complex traits. Future studies with larger sample sizes and more comprehensive genome coverage, and also in other population are required to replicate these findings.

Partial tetrasomy 11q resulting from an intrachromosomal triplication of a 22 Mb region of chromosome 11.

Intrachromosomal triplications are complex chromosomal rearrangements which arise during meiosis or mitosis and lead to a tetrasomic dose of the affected genomic regions. We describe a female patient harboring an intrachromosomal triplication who presented to the Genetics clinic with dysmorphic features, including telecanthus, flat facial profile, and prognathism, short stature, widely spaced nipples, multiple allergy complaints, loose bowel movements, and mild speech delay. Microarray analysis showed a copy number gain of a 22.37 Mb region of chromosome 11 between bands 11q14.1 and 11q22.1. This region contains 95 genes and seven microRNAs, none of which have been implicated in a disease resulting from increased gene dosage. FISH analysis using a probe targeted to the middle of the segment of the copy number gain yielded a pattern indicative of a tetrasomy via an intrachromosomal triplication, with three signals on the long arm of one homologue of chromosome 11 and the fourth on the other homologue. Subsequent FISH analysis showed that the middle triplicated fragment was positioned in an inverted orientation relative to the outer fragments. To investigate the mechanism by which the intrachromosomal triplication occurred, SNP microarray analysis was performed. These results were consistent with the presence of multiple haplotypes in the tetrasomic region and suggest that the intrachromosomal triplication in our patient arose in one parent during meiosis. © 2017 Wiley Periodicals, Inc.

Genetic response in masseter muscle after orthognathic surgery in comparison with healthy controls - A Microarray study.

One third of adult patients with orthognathic surgery of a prognathic or retrognathic mandible show relapse. The sagittal split osteotomy of the mandible leads to a displacement of both parts up to 10 mm without any changes of muscle attachment. Changed mandible length needs adaptation of muscle capacity because of changed force to moment ratio. The aim of this Microarray study was to analyze the general genetic response of masseter muscle in patients with retrognathism or prognathism of the mandible six months after surgery in comparison with healthy untreated controls. We found in tissue samples from masseter muscle a reduction of different entities between patients and controls but less in retrognathic than in prognathic patients (274/429). The different entities to controls in prognathia were reduced from 1862 to 1749 but increased in retrognathia from 1070 to 1563. We have to consider that the total amount of different entities to the controls is higher in patients with prognathic mandible (7364) because of their strong genetic controlled development compared with that in patients with retrognathic mandible (4126), which is more environmentally influenced. It can be concluded that function follows form after surgical change with high inheritance. In retrognathic patients the adaptation could be delayed or the capacity of regeneration potential is not sufficient.

Heritabilities of health traits in Swiss Warmblood horses.

REASONS FOR PERFORMING STUDY: There is a lack of evidence regarding genetic parameters of health traits in Swiss Warmblood horses. OBJECTIVES: To estimate heritabilities of equine sarcoid disease, horn quality of hooves, prognathism and increased filling of talocrural joints as a possible indicator for osteochondrosis in Swiss Warmblood horses examined at the field tests for 3-year-olds between 2005 and 2013. STUDY DESIGN: Retrospective analysis of breed society database. METHODS: Swiss Warmblood horses were examined clinically by 13 veterinarians at field tests in Switzerland between 2005 and 2013. The presence of sarcoids, horn quality of the hooves, incisor occlusion and increased joint filling were assessed and recorded. Records of 3715 horses were integrated in a pedigree comprising 217,282 horses. Variance components and heritabilities were estimated on the liability scale using multiple-trait Gibbs sampler for animal models (MTGSAM). RESULTS: The prevalences of the examined traits were rather low ranging from 2.4 to 13.0%. Heritabilities estimated were 0.21 ± 0.07 for the occurrence of sarcoids, 0.04 ± 0.02 for hooves with markedly brittle and friable horn quality, 0.03 ± 0.01 for hooves with marked growth ring formation, 0.06 ± 0.03 for prognathism and 0.08 ± 0.04 for increased filling of the talocrural joint (an indicator of possible osteochondrosis). The influence of the examiner on the variance of these observations was considerable. CONCLUSIONS: With the exception of equine sarcoid disease, estimates for the heritabilities for the traits examined here were low. A standardised examination protocol may reduce the variance due to the examiner.

Genetic Etiology in Nonsyndromic Mandibular Prognathism.

Mandibular prognathism (MP) is considered to be a cranial-facial disorder resulting from the interaction between genes and environment. Recent studies have demonstrated that susceptible chromosomal regions and candidate genes may be responsible for MP. In this study, the authors present current views on the effect of genetic components in nonsystematic mandibular prognathism, in order to clarify the genetic etiology of MP. Data source were Electronic databases, manual searching, and reference lists checking, up to April 2016. Study selection, level of evidence assessment, and data extraction were done by 2 individuals in duplicate. Ninety-one studies were retrieved in initial electronic and manual search, and based on the established inclusion and exclusion criteria, 15 were selected for the review. In result, loci 1p36, 1q32.2, 1p22.3, 4p16.1, 6q25, 19p13, 14q24.3, 14q31.1, and 14q31.2 were thought to harbor genes that confer susceptibility to MP. Genes Matrilin-1, ADAMTS1, COL2A1, and EPB41 seemed to be strongly associated with MP while gene of growth hormone receptor was in dispute. Genetic components appeared to be associated with MP. However, in view of the variety of populations and results in related publications, further studies are necessary to clarify the genetic etiology of MP.

The ADAMTS1 Gene Is Associated with Familial Mandibular Prognathism.

Mandibular prognathism is a facial skeletal malocclusion. Until now, the genetic mechanism has been unclear. The goal of this study was to identify candidate genes or genomic regions directly associated with mandibular prognathism development, by employing whole genome sequencing. A large Chinese family was recruited, composed of 9 affected and 12 unaffected individuals, and the inheritance pattern of this family tends to be autosomal dominant. A single-nucleotide missense mutation in the ADAMTS1 gene (c. 742I>T) was found to segregate in the family, given that the affected individuals must be heterozygous for the mutation. For mutation validation, we screened this candidate mutation and 15 tag single-nucleotide polymorphisms in the coding sequence of ADAMTS1 among 230 unrelated cases and 196 unrelated controls using Sequenom Massarray and found that 3 in 230 cases carried this mutation and none of the controls did. Final results suggested that 2 single-nucleotide polymorphisms (rs2738, rs229038) of ADAMTS1 were significantly associated with mandibular prognathism.

Identification of a Mutation in FGF23 Involved in Mandibular Prognathism.

Mandibular prognathism (MP) is a severe maxillofacial disorder with undetermined genetic background. We collected a Chinese pedigree with MP which involved in 23 living members of 4 generations. Genome-wide linkage analysis were carried out to obtain the information in this family and a new MP-susceptibility locus, 12pter-p12.3 was identified. Whole-exome sequencing identified a novel heterozygous mutation in fibroblast growth factor (FGF) 23 (; p.A12D) which well segregated with MP in this pedigree within the locus. The mutation was also detected in 3 cases out of 65 sporadic MP patients, but not in any of the 342 control subjects. The p.A12D mutation may disrupt signal peptide function and inhibit secretory in FGF23. Furthermore, mutant FGF23 was overexpressed in 293T cells, increased cytoplasmic accumulation was observed compared with the wild type. We have discovered that c.35C>A mutation in FGF23 strongly associated with MP, which expand our understanding of the genetic contribution to MP pathogenesis.

MicroRNA expression profile of surgical removed mandibular bone tissues from patients with mandibular prognathism.

BACKGROUND: Mandibular prognathism (MP) or skeletal class III malocclusion with a prognathic mandible is one of the most severe facial deformities. Recent work has revealed certain circulating microRNAs (miRNAs) are associated with MP, we conducted this study to characterize the miRNAs expression profile in surgically removed mandibular bone tissue in patients with MP and explored the role of miRNA regulation in the pathogenesis of MP. METHODS: Affymetrix GeneChip miRNA 3.0 Array was used to examine the miRNA expression in mandibular bone tissues from MP patients and control subjects. A variety of bioinformatic approaches were used to predict the target genes of the miRNAs, find the potential functions and pathways of the target genes, analyze their intersection with differentially expressed mRNAs, and establish miRNA-gene network. RESULTS: Eleven upregulated and 11 downregulated miRNAs with a fold change ≥ 2 and a P value <0.05 were identified in bone specimens of MP patients. A total of 3569 genes were predicted as targets of hsa-miR-10a-5p, hsa-miR-150-5p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-197-3p, hsa-miR-30 d-5p, hsa-miR-342-5p and hsa-miR-629-5p, hsa-miR-1202, and hsa-miR-638. The target genes were predicted to be involved in biological functions and signaling pathways related to osteogenesis. Hsa-miR-30 d-5p was the key node of miRNA-gene network. CONCLUSIONS: Our results indicated a possible association between the differentially expressed miRNAs and MP pathogenesis, and the precise mechanisms are needed to be further validated.

Genetic association of ARHGAP21 gene variant with mandibular prognathism.

Mandibular prognathism (MP) is a recognizable phenotype associated with dentoskeletal class III malocclusion. MP is a complex genetic trait, although familial recurrence also suggests the contribution of single inherited variations. To date, the genetic causes of MP have been investigated using linkage analysis or association studies in pooled families. Here for the first time, next-generation sequencing was used to study a single family with a large number of MP-affected members and to identify MP-related candidate genes. A 6-generation kindred with MP segregating as an autosomal dominant character was recruited. To identify family members affected by MP, a standard cephalometric procedure was used. In 5 MP subjects separated by the largest number of meioses, whole-exome sequencing was performed. Five promising missense gene variants (BMP3, ANXA2, FLNB, HOXA2, and ARHGAP21) associated with MP were selected and genotyped in most other family members. In this family, MP seemed to consist of 2 distinct genetic branches. Interestingly, the Gly1121Ser variant in the ARHGAP21 gene was found to be shared by all MP individuals in the larger branch of the family with nearly complete penetrance. This variant is rare in the Caucasian population (frequency 0.00034) and is predicted as damaging by all bioinformatic algorithms. ARHGAP21 protein strengthens cell-cell adhesions and may be regulated by bone morphogenetic factors, thus influencing mandibular growth. Further studies in both animal models and human patients are required to clarify the significance of this association.

Microsatellite genome-wide association study for mandibular prognathism.

INTRODUCTION: Attempts have been made to identify susceptibility genes of mandibular prognathism by genome-wide linkage studies, but the results of susceptibility loci are inconsistent. There has been no genome-wide association study of mandibular prognathism. Our objective was to perform a genome-wide association study using 23,465 microsatellite markers to detect mandibular prognathism susceptibility regions. METHODS: The study was based on the pooled DNA method, including 2 steps of screening on the whole genome and subsequent individual genotyping, with 240 experimental subjects and 360 control subjects from the Japanese population. RESULTS: Two suggestive associations on chromosomes 1q32.2 (D1S1358i: P = 4.22 × 10(-4)) and 1p22.3 (D1S0411i: P = 6.66 × 10(-4)) were shown, and PLXNA2 and SSX2IP were suggested to be candidate genes; 1p22.3 flanked the region indicated by previous linkage analysis. CONCLUSIONS: The results of the genome-wide association study showed that 2 loci (1q32.2 and 1p22.3) are likely to be susceptibility regions of mandibular prognathism: 1p32.2 is a novel locus, and identification of 1p22.3 supports the results of previous linkage analysis.