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1.
Sci Rep ; 11(1): 748, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436952

RESUMO

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.

2.
Nat Genet ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288918

RESUMO

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33368457

RESUMO

OBJECTIVES: This cross-sectional study assessed differences in oral health and related behaviours and risk indicators by rurality in a north-central Appalachian population using the Andersen behavioural model as a conceptual framework. METHODS: Participants were residents aged 18-59 years (n = 1311) from the Center for Oral Health Research in Appalachia, selected according to a household-based sampling strategy. Rural-Urban Continuum codes (RUC) corresponding to the participants' residences were used to classify participants as rural or urban. Mixed models were used to test rural-urban differences in measures of oral health, related behaviours, and need, enabling, and predisposing risk indicators. Models were adjusted for sociodemographic variables: age, sex, race, income, perceived socioeconomic status, educational attainment and dental insurance. RESULTS: Rural residents had poorer oral health overall, with fewer sound teeth (ß = -1.79), more dental caries (ß = 0.27) and higher rates of edentulism (5.2% vs 2.8%). Differences also were observed for dental care utilization and perceived barriers to care. Rural residents were less likely to attend dental visits as often as needed (26.9% vs 42.8%) and were more prone to seek care only after experiencing a dental problem (64.3% vs 43.9%). Rural residents also were more likely to report high costs (89% vs 62.6%) as a major reason for not having dental visits. Rural-urban differences for some oral health characteristics and behaviours could be explained by sociodemographic characteristics, whereas others could not. CONCLUSIONS: This study revealed rural-urban differences in risk indicators and oral health outcomes in north-central Appalachia. Many of these differences were explained, completely or partly, by sociodemographic factors.

4.
Nat Commun ; 11(1): 5562, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144568

RESUMO

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.


Assuntos
Predisposição Genética para Doença , Característica Quantitativa Herdável , Tabagismo/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança/genética , Desequilíbrio de Ligação/genética , Metanálise como Assunto , Anotação de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
5.
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.

6.
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.

7.
Sci Rep ; 10(1): 14640, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887894

RESUMO

Salivary microbiome composition can change following exposure to environmental toxicants, e.g., heavy metals. We hypothesized that levels of salivary nutrients and metals would correlate with salivary microbiome composition and be associated with dental decay. Here we assess the salivary concentrations of 5 essential minerals (cobalt, copper, manganese, molybdenum, and zinc), 4 metals with some evidence of normal physiological function (chromium, nickel, tungsten, and vanadium), and 12 with known toxicity (antimony, arsenic, barium, beryllium, cadmium, cesium, lead, mercury, platinum, thallium, tin, and uranium), and their associations with salivary microbiome composition and dental decay in 61 children and adults. 16 metals were detected in 54% of participants; 8 were found in all. Marked differences in salivary bacterial taxa were associated with levels of antimony, arsenic, and mercury, after adjusting for multiple testing. Further, antimony levels were associated with the presence of decayed teeth. Thus, salivary metal levels, even at low concentrations, may impact oral health.

8.
Development ; 147(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958507

RESUMO

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a 'big data' resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

9.
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
10.
Mol Genet Genomic Med ; 8(8): e1355, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32558391

RESUMO

BACKGROUND: The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7-9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. METHODS: We used PubMed with the search terms; "Van der Woude syndrome," "Popliteal pterygium syndrome," "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. RESULTS: Twenty-one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7-9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7-9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). CONCLUSION: Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

11.
J Oral Microbiol ; 12(1): 1746494, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32363007

RESUMO

Objective: The interactions between yeast and streptococci species that lead to dental decay and gingivitis are poorly understood. Our study describes these associations among a cohort of 101 post-partum women enrolled in the Center for Oral Health Research in Appalachia, 2012-2013. Methods: All eligible women without dental caries were included (n = 21) and the remainder were randomly sampled to represent the total number of decayed, missing, and filled teeth (DMFT) at enrollment. We used amplicon sequencing and qPCR of saliva from 2, 6, 12 and 24 visits to determine microbiome composition. Results: Active decay and generalized gingivitis were strongly predictive of each other. Using adjusted marginal models, Candida albicans and Streptococcus mutans combined were associated with active decay (OR = 3.13; 95% CI 1.26, 7.75). However, C. albicans alone (OR = 2.33; 95% CI: 0.81, 6.75) was associated with generalized gingivitis, but S. mutans alone was not (OR = 0.55; 95% CI: 0.21, 1.44). Models including microbiome community state types (CSTs) showed CSTs positively associated with active decay were negatively associated with generalized gingivitis. Discussion: C. albicans is associated with active decay and generalized gingivitis, but whether one or both are present depends on the structure of the co-existing microbial community.

12.
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.

13.
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
14.
Laryngoscope ; 130(2): 533-540, 2020 02.
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.


Assuntos
Fenda Labial , Fissura Palatina , Tomografia Computadorizada de Feixe Cônico , Imageamento Tridimensional , Faringe/anatomia & histologia , Faringe/diagnóstico por imagem , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Japão , Masculino , Estudos Retrospectivos
15.
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
16.
J Clin Densitom ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31668963

RESUMO

The foundation for osteoporosis risk is, in part, established during childhood, adolescence, and young adulthood, all periods of development when bone mass is acquired rapidly. The relative quantity of bone mass accrued is influenced by both lifestyle and genetic factors, although the genetic component is not yet well understood. The purpose of this study was to use a genome-wide association (GWA) analysis to discover single nucleotide polymorphisms (SNPs) associated with: (1) the sex-specific hip bone mineral content at approximately the age of 19 when the amount of bone accrued is near its peak; and (2) the sex-specific rate of hip bone mineral content accrual during the adolescent growth spurt. The Iowa Bone Development Study, a longitudinal cohort study exploring bone health in children, adolescents, and young adults was the source of data. From this cohort, n = 364 (190 females, 174 males) participants were included in GWA analyses to address (1) and n = 258 participants (125 females and 133 males) were included in GWA analyses to address (2). Twenty SNPS were detected having p < 1.0 × 10-5. Of most biologic relevance were 2 suggestive SNPs (rs2051756 and rs2866908) detected in an intron of the DKK2 gene through the GWA analysis that explored peak bone mass in females.

17.
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
18.
Nat Commun ; 10(1): 3927, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.


Assuntos
Cromossomos Humanos Par 2/genética , Citocinas/genética , Feto/metabolismo , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/genética
19.
Int J Paediatr Dent ; 29(6): 720-727, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328316

RESUMO

BACKGROUND: Dental fear/anxiety is associated with numerous negative outcomes. State dental fear is known to be transmitted from parents to their children in the dental setting, but it is not known how trait fear/anxiety might be shared between parents and offspring long term, and especially for adolescents. AIM: This study aimed to: (a) compare dental fear levels of adolescents and their parents; (b) predict adolescent dental fear based on demographic variables, fear of pain, and parental dental fear; and, (c) determine relative contributions of mothers' and fathers' dental fear to adolescent fear. DESIGN: In this cross-sectional study, the Dental Fear Survey and Fear of Pain Questionnaire-9 were administered to 350 adolescents (age range 11-17) and 515 of their parents, with t test and ANOVA used to calculate between-group differences; multiple linear regression was used to predict adolescent fear from parent fear. RESULTS: Adolescents' dental fear was predicted by their own fear of pain and their parents' dental fear, but not their parents' fear of pain nor their own age or gender. When considered together, fathers' but not mothers' dental fear predicted adolescents' dental fear. CONCLUSIONS: Parents' fears/anxieties about dentistry are associated with adolescents' dental fear in a manner suggestive of intergenerational transmission.


Assuntos
Ansiedade ao Tratamento Odontológico , Pais , Adolescente , Criança , Estudos Transversais , Pai , Feminino , Humanos , Masculino , Mães , Relações Pais-Filho
20.
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
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