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1.
Homo ; 71(4): 273-280, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33146661

RESUMO

Objectives: Torus Palatinus (TP) is a bony projection located on the oral surface of the hard palate. The trait is typically benign, has an unknown etiology, and varies widely in phenotypic expression. Prior studies suggest differences in TP prevalence by sex and ancestry, but the reported rates vary, even within a single ancestral group. We assessed the prevalence of TP and its association with palatal shape in a large multi-ethnic cohort of normal individuals. Methodology: 1102 adults were included (625 with European ancestry, 377 with West African anscestry, and 100 with East Asian ancestry). 3D digital dental casts were obtained and rated. TP frequencies were compared between sexes and/or ethnicities using Chi-squared tests. Dental cast models were then landmarked, and canonical variates analysis was performed to test for shape differences between those with and without TP. Results: Females had a significantly higher rate of TP than males across all three ancestral groups (p≤0.004). In males, no significant differences were found among ethnicities. Ancestral differences in TP frequency were driven by females, with East Asians having the highest rate (34.69%), followed by Europeans (24.88%) and West Africans (15.22%). Shape differences were found only in Asians and Africans, indicated a shorter and wider palate in presence of TP. Conclusions: Ethnic differences in TP frequency were present only in females. Further, females have considerably higher rates of TP than males in each population tested. Further studies of TP at earlier time-points and in connection to other aspects of craniofacial growth may shed light on these sex and ethnic differences.

2.
Cleft Palate Craniofac J ; : 1055665620967235, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33111571

RESUMO

OBJECTIVE: The unaffected relatives of individuals with nonsyndromic orofacial clefts have been shown to exhibit subtle craniofacial differences compared with the general population. Here, we investigate whether these morphological differences extend to the shape of the palate. DESIGN: We conducted a geometric morphometric analysis to compare palate shape in the clinically unaffected parents of children with nonsyndromic cleft lip with or without cleft palate and adult controls of European, Asian, and African ancestry. We conducted pairwise group comparisons using canonical variates analysis, and then confirmed and characterized findings of shape differences using Euclidean distance matrix analysis. RESULTS: Significant differences in palate shape were detected in unaffected mothers (but not fathers) compared to demographically matched controls. The differences in shape were ancestry-specific; mothers of Asian-derived and African-derived ancestry showed wider and shorter palates with higher posterior palatal vaults, while mothers of European-derived ancestry showed narrower palates with higher anterior palatal vaults. CONCLUSIONS: Our findings suggest that altered palate shape is a subclinical phenotypic feature, which may be indicative of elevated orofacial cleft risk. The risk phenotype varied by sex and ancestry, suggesting possible etiologic heterogeneity among demographic groups. Understanding the genetic basis of these informative palate shape traits may reveal new genes and pathways relevant to nonsyndromic orofacial clefting.

3.
Am J Hum Genet ; 107(1): 124-136, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32574564

RESUMO

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/genética , Mutação/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Genoma/métodos
4.
Int J Epidemiol ; 49(4): 1282-1293, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32373937

RESUMO

BACKGROUND: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. RESULTS: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (ßMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; ßMR -0.009, 95% CI -0.02 to 0.002, P 0.11). CONCLUSIONS: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

5.
Mol Genet Genomic Med ; 8(7): e1251, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32347019

RESUMO

BACKGROUND: Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix protein primarily functioning in the musculoskeletal tissues and especially endochondral bone growth. Mutations in COMP cause the skeletal dysplasia pseudoachondroplasia (PSACH) that is characterized by short limbs and fingers, joint laxity, and abnormalities but a striking lack of skull and facial abnormalities. METHODS: This study examined both mice and humans to determine how mutant-COMP affects face and skull growth. RESULTS: Mutant COMP (MT-COMP) mice were phenotypically distinct. Snout length and skull height were diminished in MT-COMP mouse and the face more closely resembled younger controls. Three-dimensional facial measurements of PSACH faces showed widely spaced eyes, reduced lower facial height, and decreased nasal protrusion, which correlated with a more juvenile appearing face. Neither MT-COMP mice nor PSACH individuals show midface hypoplasia usually associated with abnormal endochondral bone growth. MT-COMP mice do show delayed endochondral and membranous skull ossification that normalizes with age. CONCLUSION: Therefore, mutant-COMP affects both endochondral and intramembranous bones of the skull resulting in a reduction of the nose and lower facial height in mice and humans, in addition to its well-defined role in the growth plate chondrocytes.

6.
PLoS One ; 15(3): e0230534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196525

RESUMO

Dermatoglyphic patterns on the fingers often differ in syndromes and other conditions with a developmental component, compared to the general population. Previous literature on the relationship between orofacial clefts-the most common craniofacial birth defect in humans-and dermatoglyphics is inconsistent, with some studies reporting altered pattern frequencies and/or increased asymmetry and others failing to find differences. To investigate dermatoglyphics in orofacial clefting, we obtained dermatoglyphic patterns in a large multiethnic cohort of orofacial cleft cases (N = 367), their unaffected family members (N = 836), and controls (N = 299). We categorized fingerprint pattern types from males and females who participated at five sites of the Pittsburgh Orofacial Cleft study (Hungary, United States of America (Pennsylvania, Texas), Spain, and Argentina). We also calculated a pattern dissimilarity score for each individual as a measure of left-right asymmetry. We tested for group differences in the number of arches, ulnar and radial loops, and whorls on each individual's hands, and in the pattern dissimilarity scores using ANOVA. After taking sex and site differences into account, we did not find any significant pattern count differences between cleft and non-cleft individuals. Notably, we did observe increased pattern dissimilarity in individuals with clefts, compared to both their unaffected relatives and controls. Increased dermatoglyphic pattern dissimilarity in individuals with nonsyndromic orofacial clefts may reflect a generalized developmental instability.


Assuntos
Encéfalo/anormalidades , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Dermatoglifia , Análise de Variância , Fenda Labial/genética , Fissura Palatina/genética , Estudos de Coortes , Família , Feminino , Humanos , Masculino , Fenótipo , Fatores Sexuais
7.
Laryngoscope ; 130(2): 533-540, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30977521

RESUMO

OBJECTIVES/HYPOTHESIS: Individuals with orofacial clefts often experience respiratory problems because of nasopharyngeal abnormalities. Pharyngeal airway morphology is thought to differ among the various cleft types. We measured three-dimensional (3D) airway volume using cone-beam computed tomography (CBCT) analysis to evaluate and compare pharyngeal airways in Japanese preschoolers with and without orofacial clefts. STUDY DESIGN: Retrospective case-control study. METHODS: We enrolled 83 subjects (37 boys, 46 girls; mean age = 4.66 ± 0.56 years) with nonsyndromic orofacial clefts and 16 noncleft healthy subjects (seven boys, nine girls; mean age = 5.30 ± 0.52 years) as controls. The subjects were divided into five groups. Four groups were based on the cleft type: isolated cleft palate, unilateral cleft lip and alveolus), unilateral cleft lip and palate, and bilateral cleft lip and palate. The fifth group included the noncleft controls. All subjects were examined with CBCT, and the 3D airway volume was measured. We analyzed group differences statistically using analysis of covariance with the Bonferroni post hoc pairwise comparison tests for the corrected means. RESULTS: Compared with the noncleft group, each cleft group exhibited significantly decreased total and nasal airway volumes and increased superior and inferior pharyngeal airway volumes. The differences were all statistically significant. CONCLUSIONS: Our findings suggest that anatomical differences exist in pharyngeal airway volumes among various cleft groups and in those without a cleft. LEVEL OF EVIDENCE: 3b Laryngoscope, 130:533-540, 2020.

8.
Hum Genet ; 139(2): 215-226, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848685

RESUMO

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.


Assuntos
Cromossomos Humanos Par 21/genética , Fenda Labial/genética , Fissura Palatina/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Criança , Colômbia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
9.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
10.
Genet Epidemiol ; 43(6): 704-716, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172578

RESUMO

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.


Assuntos
Encéfalo/anormalidades , Fenda Labial/classificação , Fenda Labial/genética , Fissura Palatina/classificação , Fissura Palatina/genética , Loci Gênicos , Marcadores Genéticos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Encéfalo/patologia , Fenda Labial/patologia , Fissura Palatina/patologia , Humanos , Transcriptoma
11.
Nat Commun ; 10(1): 2557, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186421

RESUMO

Facial recognition from DNA refers to the identification or verification of unidentified biological material against facial images with known identity. One approach to establish the identity of unidentified biological material is to predict the face from DNA, and subsequently to match against facial images. However, DNA phenotyping of the human face remains challenging. Here, another proof of concept to biometric authentication is established by using multiple face-to-DNA classifiers, each classifying given faces by a DNA-encoded aspect (sex, genomic background, individual genetic loci), or by a DNA-inferred aspect (BMI, age). Face-to-DNA classifiers on distinct DNA aspects are fused into one matching score for any given face against DNA. In a globally diverse, and subsequently in a homogeneous cohort, we demonstrate preliminary, but substantial true (83%, 80%) over false (17%, 20%) matching in verification mode. Consequences of future efforts include forensic applications, necessitating careful consideration of ethical and legal implications for privacy in genomic databases.


Assuntos
Identificação Biométrica , Face/anatomia & histologia , Reconhecimento Facial , Genótipo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estatura , Peso Corporal , Estudos de Coortes , Bases de Dados de Ácidos Nucleicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Orthod Craniofac Res ; 22 Suppl 1: 207-212, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31074157

RESUMO

There is ample evidence from heritability studies, genetic syndromes and experimental animal models that facial morphology is strongly influenced by genes. In this brief review, we present an up-to-date overview of the efforts to identify genes associated with the size and shape of human facial features. We discuss recent methodological advances that have led to breakthroughs, but also the multitude of challenges facing the field. We offer perspective on possible applications of this line of research, particularly in the context of the precision genomics movement.


Assuntos
Estudo de Associação Genômica Ampla , Genômica , Genótipo , Humanos , Fenótipo
13.
Am J Orthod Dentofacial Orthop ; 155(5): 693-701, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31053285

RESUMO

INTRODUCTION: Datasets of soft-tissue craniofacial anthropometric norms collected with the use of different methods are available, but there is little understanding of how the measurements compare. Here we compare a set of standard facial measurements between 2 large datasets: the 3D Facial Norms (3DFN) dataset collected with the use of 3D stereophotogrammetry (n = 2454), and the Farkas craniofacial norms collected with the use of direct anthropometry (n = 2326). METHODS: A common set of 24 craniofacial linear distances were compared by computing standardized effect sizes (Cohen d) for each measurement to describe the overall direction and magnitude of the difference between the 2 datasets. RESULTS: Variables with higher mean d values (suggesting greater discrepancy across datasets) included measurements involving the ear landmark tragion, the landmark nasion, the width of nasolabial structures, the vermilion portion of the lips, and palpebral fissure length. Variables with lower mean d values included smaller midline measurements involving the lips and lower face and horizontal distance measures between the eyes. Eight measurements showed a significant negative correlation (P < 0.05) between Cohen d and age, indicating greater similarity across the 2 datasets as age increased. CONCLUSIONS: There are considerable differences between the 3DFN and Farkas norms. In addition to the measurement methods, other factors accounting for discrepancies may include secular trends in craniofacial morphology or differences in ethnic composition.


Assuntos
Antropometria/métodos , Face/anatomia & histologia , Imageamento Tridimensional , Fotogrametria/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Bases de Dados Factuais , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , América do Norte , Valores de Referência
14.
Am J Med Genet A ; 179(3): 467-474, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30582786

RESUMO

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value = .001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.


Assuntos
Encéfalo/anormalidades , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Sequências Reguladoras de Ácido Nucleico , Alelos , Elementos Facilitadores Genéticos , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
15.
Front Genet ; 9: 497, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405702

RESUMO

Many factors influence human facial morphology, including genetics, age, nutrition, biomechanical forces, and endocrine factors. Moreover, facial features clearly differ between males and females, and these differences are driven primarily by the influence of sex hormones during growth and development. Specific genetic variants are known to influence circulating sex hormone levels in humans, which we hypothesize, in turn, affect facial features. In this study, we investigated the effects of testosterone-related genetic variants on facial morphology. We tested 32 genetic variants across 22 candidate genes related to levels of testosterone, sex hormone-binding globulin (SHGB) and dehydroepiandrosterone sulfate (DHEAS) in three cohorts of healthy individuals for which 3D facial surface images were available (Pittsburgh 3DFN, Penn State and ALSPAC cohorts; total n = 7418). Facial shape was described using a recently developed extension of the dense-surface correspondence approach, in which the 3D facial surface was partitioned into a set of 63 hierarchically organized modules. Each variant was tested against each of the facial surface modules in a multivariate genetic association-testing framework and meta-analyzed. Additionally, the association between these candidate SNPs and five facial ratios was investigated in the Pittsburgh 3DFN cohort. Two significant associations involving intronic variants of SHBG were found: both rs12150660 (p = 1.07E-07) and rs1799941 (p = 6.15E-06) showed an effect on mandible shape. Rs8023580 (an intronic variant of NR2F2-AS1) showed an association with the total and upper facial width to height ratios (p = 9.61E-04 and p = 7.35E-04, respectively). These results indicate that testosterone-related genetic variants affect normal-range facial morphology, and in particular, facial features known to exhibit strong sexual dimorphism in humans.

16.
Front Genet ; 9: 502, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410503

RESUMO

Objectives: Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. In this study, we investigated the influence of genetic variants associated with NSCL/P on normal-range variation in facial shape. Methods: A literature review of genome wide association studies (GWAS) investigating the genetic etiology of NSCL/P was performed, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically-constructed facial segments in each of the three datasets and meta-analyzed. This allowed for the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics. Results: Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (p = 3.71 × 10-28). This SNP lies in a non-coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 × 10-16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 × 10-14), rs34246903 (p = 6.87 × 10-12), and rs10512248 (p = 8.4 × 10-9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 × 10-7). Conclusions: This study provides additional evidence NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area.

17.
PLoS Genet ; 14(10): e1007675, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30286078

RESUMO

The mechanisms that regulate post-natal growth of the craniofacial complex and that ultimately determine the size and shape of our faces are not well understood. Hippo signaling is a general mechanism to control tissue growth and organ size, and although it is known that Hippo signaling functions in neural crest specification and patterning during embryogenesis and before birth, its specific role in postnatal craniofacial growth remains elusive. We have identified the transcription factor FoxO6 as an activator of Hippo signaling regulating neonatal growth of the face. During late stages of mouse development, FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Enlargement of the mandible and maxilla and lengthening of the incisors in FoxO6-/- mice are associated with increases in cell proliferation. In vitro and in vivo studies demonstrated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling. FoxO6-/- mice have significantly reduced Hippo Signaling caused by a decrease in Lats1 expression and decreases in Shh and Runx2 expression, suggesting that Shh and Runx2 are also linked to Hippo signaling. In vitro, FoxO6 activates Hippo reporter constructs and regulates cell proliferation. Furthermore PITX2, a regulator of Hippo signaling is associated with Axenfeld-Rieger Syndrome causing a flattened midface and we show that PITX2 activates FoxO6 expression. Craniofacial specific expression of FoxO6 postnatally regulates Hippo signaling and cell proliferation. Together, these results identify a FoxO6-Hippo regulatory pathway that controls skull growth, odontogenesis and face morphology.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Desenvolvimento Maxilofacial/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Crânio/crescimento & desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Proteínas de Homeodomínio/metabolismo , Desenvolvimento Maxilofacial/genética , Camundongos , Crista Neural/citologia , Tamanho do Órgão , Fosforilação , Transdução de Sinais , Crânio/metabolismo , Fatores de Transcrição/metabolismo
18.
Genet Epidemiol ; 42(7): 664-672, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30277614

RESUMO

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.


Assuntos
Alelos , Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Caracteres Sexuais , Estudos de Casos e Controles , Epistasia Genética , Feminino , Frequência do Gene/genética , Loci Gênicos , Humanos , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Arch Oral Biol ; 96: 33-38, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30172943

RESUMO

OBJECTIVE: The aim of the present study is to explore genetic factors determining difference of cleft side using whole-genome sequencing and evaluation of craniofacial morphology using cephalometric analysis between Japanese monozygotic (MZ) twins with mirror-image cleft lip and palate (CLP). DESIGN: We selected a Japanese MZ twin pair (MZ-A and MZ-B) affected with unilateral CLP who are discordant for cleft side (left/right) and conducted whole-genome sequencing to identify genetic factors determining cleft side. Moreover, we compared their craniofacial morphologies using cephalograms. RESULTS: Whole-genome sequencing results suggested that no discordant DNA variants were found between MZ-A and MZ-B. The comparison of craniofacial morphology between the MZ twins revealed that MZ-B had maxillary deficiency and slightly more mandibular protrusion than MZ-A. CONCLUSIONS: It is indicated that environmental factors might be a critical factor that influences the determination of difference of cleft side in orofacial clefts. In addition, we found some differences in craniofacial morphology between MZ-A and MZ-B. Our findings suggest that various environmental factors, such as epigenetics, might be a critical factor that influences the determination of difference of cleft side in CLP rather than inherited genetic factors.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Doenças em Gêmeos/genética , Alelos , Cefalometria , Pré-Escolar , Genótipo , Humanos , Japão , Masculino , Análise de Sequência de DNA , Gêmeos Monozigóticos
20.
PLoS Genet ; 14(8): e1007501, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30067744

RESUMO

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Lábio/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Grupos de Populações Continentais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Estudos Longitudinais , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
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