Maternal perceptions of assisting preschool-aged children with toothbrushing.

BACKGROUND: Parent-led toothbrushing with fluoride toothpaste is part of an evidence-based strategy to prevent caries in children. There is a gap in the literature regarding perceptions of how and when to assist a child with toothbrushing from the maternal perspective. METHODS: A qualitative cross-sectional study was conducted with participants in North and North Central Appalachia to examine maternal perceptions of when and how to assist with toothbrushing. From 2018 through 2022, 301 mothers of children aged 3 through 5 years volunteered to participate in semistructured interviews from a more extensive parent study (Center for Oral Health Research in Appalachia cohort). The qualitative data were transcribed, coded, and analyzed using Nvivo software, Version 12 (QSR International). The data were analyzed using grounded theory, constant comparative method, and template analysis. RESULTS: A total of 301 mothers were interviewed for this study; 156 (52%) lived in West Virginia and 145 (48%) lived in Pittsburgh, Pennsylvania. Four main themes emerged: (1) assisting with child toothbrushing, (2) ceasing to provide assistance with child toothbrushing, (3) lacking recommendations from dental care professionals on child toothbrushing, and (4) adhering to recommendations from dental care professionals on child toothbrushing assistance. CONCLUSIONS: Understanding the factors that influence how parents brush their children's teeth and the information they receive to guide daily dental hygiene behavior for children is essential in developing effective interventions for preventing caries in children. PRACTICAL IMPLICATIONS: These insights can improve child toothbrushing quality through improved oral hygiene education, recommendations, terminology, and policies from the dental community.

Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis.

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

Risk of Postpartum Dental Caries: Survival Analysis of Black/African American and White Women in Appalachia.

Background: Pregnancy is associated with increased risk of caries, but the extent this increase extends into the postpartum period is poorly understood. Study Objective: Describe the epidemiology of dental decay in the postpartum period among Black/African American and White American women and explore associations with potentially modifiable risk factors. Materials and Methods: We analyzed data from 1,131 Black/African American and White women participating in Center for Oral Health Research in Appalachia cohorts. Women were enrolled during the first two trimesters of pregnancy. Calibrated dental professionals completed dental examinations at the prenatal enrollment visit, and 2-month, 1-year, 2-year, and 3-year postpartum visits. Results: Between the prenatal visit and 2-month visit, the incidence of decayed, missing, and filled teeth (DMFT) increase was 6.92/100 person-months, compared to 3.6/100 person-months between the 2-month and 1-year visit. In a multivariate Cox proportional hazard regression predicting incidence of caries up to 3-years postpartum, being younger, having less than college education, a household income <$50,000, smoking cigarettes, a DMFT >0, a very poor or poor Oral hygiene Rating Index, lower salivary pH at enrollment, or frequently drinking 100% juice increased the hazard of new dental caries. Adjusting for race/ethnic group did not affect the direction or magnitude of observed associations. Conclusions: The strong associations of prior DMFT and Oral Rating Index with occurrence of new dental caries postpartum suggests that targeting young women for interventions to improve oral health may be more valuable for reducing caries incidence during pregnancy and in the postpartum period than targeting women only during pregnancy.

Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

Sex Differences in Velopharyngeal Anatomy of 9- and 10-Year-Old Children.

OBJECTIVE: Understanding the normal anatomy of velopharyngeal (VP) mechanism and the emergence of sexual dimorphism provides valuable insights into differences of VP anatomy among males and females. The purpose of this study is to examine sex differences in VP anatomy in a large data set of 3,248 9- and 10-year-old children. METHOD: Static three-dimensional magnetic resonance imaging was used to compare five VP characteristics including velar length, velar thickness, effective velar length, levator veli palatini muscle length, and pharyngeal depth between age-matched males (n = 1,670) and females (n = 1,578). Additionally, these dimensions were used to determine the VP ratio and effective VP ratio. RESULTS: Males showed significantly larger dimensions for all VP distances and significantly lower ratios of velar length and effective velar length to pharyngeal depth (p < .05). The magnitude of these effect sizes was small to medium, with Cohen's d values ranging from 0.12 to 0.63. Additionally, the VP ratio and effective VP ratio are lower among males compared to females (p < .05). CONCLUSIONS: Results suggest the presence of sexual dimorphism in the VP mechanism among 9- and 10-year-old children. These findings emphasize the necessity of using different normative data for males and females when making comparisons to patients with cleft palate.

Potential risk factors and genetic variants associated with dental caries incidence in Appalachia using genome-wide survival analysis.

OBJECTIVE: The aim of this study was to identify the potential risk factors and genetic variants associated with dental caries incidence using survival analysis. METHODS: The Center for Oral Health Research in Appalachia recruited and prospectively followed pregnant women and their children. A total of 909 children followed from birth for up to 7 years were included in this study. Annual intra-oral examinations were performed to assess dental caries experience including the approximate time to first caries incidence in the primary dentition. Cox proportional hazards models were used to assess the associations of time to first caries incidence with self-reported risk factors and 4.9 million genetic variants ascertained using a genome-wide genotyping array. RESULTS: A total of 196 of 909 children (21.56%) had their first primary tooth caries event during follow-up. Household income, home water source, and mother's educational attainment were significantly associated with time to first caries incidence in the stepwise Cox model. The heritability (i.e., proportion of variance explained by genetics) of time to first caries was 0.54. Though no specific genetic variants were associated at the genome-wide significance level (P < 5E-8), we identified 14 loci at the suggestive significance level (5E-8 < P < 1E-5), some of which were located within or near genes with plausible biological functions in dental caries. CONCLUSION: Our findings indicate that household income, home water source, and mother's educational attainment are independent risk factors for dental caries incidence. We nominate several suggestive loci for further investigation.

Data-driven trait heritability-based extraction of human facial phenotypes.

A genome-wide association study (GWAS) of a complex, multi-dimensional morphological trait, such as the human face, typically relies on predefined and simplified phenotypic measurements, such as inter-landmark distances and angles. These measures are predominantly designed by human experts based on perceived biological or clinical knowledge. To avoid use handcrafted phenotypes (i.e., a priori expert-identified phenotypes), alternative automatically extracted phenotypic descriptors, such as features derived from dimension reduction techniques (e.g., principal component analysis), are employed. While the features generated by such computational algorithms capture the geometric variations of the biological shape, they are not necessarily genetically relevant. Therefore, genetically informed data-driven phenotyping is desirable. Here, we propose an approach where phenotyping is done through a data-driven optimization of trait heritability, defined as the degree of variation in a phenotypic trait in a population that is due to genetic variation. The resulting phenotyping process consists of two steps: 1) constructing a feature space that models shape variations using dimension reduction techniques, and 2) searching for directions in the feature space exhibiting high trait heritability using a genetic search algorithm (i.e., heuristic inspired by natural selection). We show that the phenotypes resulting from the proposed trait heritability-optimized training differ from those of principal components in the following aspects: 1) higher trait heritability, 2) higher SNP heritability, and 3) identification of the same number of independent genetic loci with a smaller number of effective traits. Our results demonstrate that data-driven trait heritability-based optimization enables the automatic extraction of genetically relevant phenotypes, as shown by their increased power in genome-wide association scans.

Bacterial community modifies host genetics effect on early childhood caries.

Background: By age five approximately one-fifth of children have early childhood caries (ECC). Both the oral microbiome and host genetics are thought to influence susceptibility. Whether the oral microbiome modifies genetic susceptibility to ECC has not been tested. We test whether the salivary bacteriome modifies the association of a polygenic score (PGS, a score derived from genomic data that summarizes genetic susceptibility to disease) for primary tooth decay on ECC in the Center for Oral Health Research in Appalachia 2 longitudinal birth cohort. Methods: Children were genotyped using the Illumina Multi-Ethnic Genotyping Array and underwent annual dental examinations. We constructed a PGS for primary tooth decay using weights from an independent, genome-wide association meta-analysis. Using Poisson regression, we tested for associations between the PGS (high versus low) and ECC incidence, adjusting for demographic characteristics (n=783). An incidence-density sampled subset of the cohort (n=138) had salivary bacteriome data at 24- months of age. We tested for effect modification of the PGS on ECC case status by salivary bacterial community state type (CST). Results: By 60-months, 20.69% of children had ECC. High PGS was not associated with an increased rate of ECC (incidence-rate ratio:1.09 (95% confidence interval (CI): 0.83, 1.42)). However, having a cariogenic salivary bacterial CST at 24-months was associated with ECC (odds ratio (OR): 7.48 (95%CI: 3.06, 18.26)), which was robust to PGS adjustment. An interaction existed between the salivary bacterial CST and the PGS on the multiplicative scale (P= 0.04). The PGS was associated with ECC (OR: 4.83 (95% CI: 1.29, 18.17)) only among individuals with a noncariogenic salivary bacterial CST (n=70). Conclusions: Genetic causes of caries may be harder to detect when not accounting for cariogenic oral microbiomes. As certain salivary bacterial CSTs increased ECC-risk across genetic-risk strata, preventing colonization of cariogenic microbiomes would be universally beneficial.

Exploring regional aspects of 3D facial variation within European individuals.

Facial ancestry can be described as variation that exists in facial features that are shared amongst members of a population due to environmental and genetic effects. Even within Europe, faces vary among subregions and may lead to confounding in genetic association studies if unaccounted for. Genetic studies use genetic principal components (PCs) to describe facial ancestry to circumvent this issue. Yet the phenotypic effect of these genetic PCs on the face has yet to be described, and phenotype-based alternatives compared. In anthropological studies, consensus faces are utilized as they depict a phenotypic, not genetic, ancestry effect. In this study, we explored the effects of regional differences on facial ancestry in 744 Europeans using genetic and anthropological approaches. Both showed similar ancestry effects between subgroups, localized mainly to the forehead, nose, and chin. Consensus faces explained the variation seen in only the first three genetic PCs, differing more in magnitude than shape change. Here we show only minor differences between the two methods and discuss a combined approach as a possible alternative for facial scan correction that is less cohort dependent, more replicable, non-linear, and can be made open access for use across research groups, enhancing future studies in this field.

Genome-Wide Analysis of Dental Caries Variability Reveals Genotype-by-Environment Interactions.

Genotype-by-environment interactions (GEI) may influence dental caries, although their effects are difficult to detect. Variance quantitative trait loci (vQTL) may serve as an indicator of underlying GEI effects. The aim of this study was to investigate GEI effects on dental caries by prioritizing variants from genome-wide vQTL analysis. First, we identified vQTLs from ~4.3 M genome-wide variants in three cohorts of white children aged 3-5 (n = 396, n = 328, n = 773) using Levene's test. A total of 39 independent vQTLs with p < 1 × 10-6 were identified, some of which were located in or near genes with plausible biological roles in dental caries (IGFBP7, SLC5A8, and SHH involved in tooth development and enamel mineralization). Next, we used linear regression to test GEI effects on dental caries with the 39 prioritized variants and self-reported environmental factors (demographic, socioeconomic, behavioral, and dietary factors) in the three cohorts separately. We identified eight significant GEIs indicating that children with vQTL risk genotypes had higher caries experience if they had less educated parents, lower household/parental income, brushed their teeth less frequently, consumed sugar-sweetened beverages more frequently, were not breastfed, and were female. We reported the first genome-wide vQTL analysis of dental caries in children nominating several novel genes and GEI for further investigations.

Using data-driven phenotyping to investigate the impact of sex on 3D human facial surface morphology.

The effects of sex on human facial morphology have been widely documented. Because sexual dimorphism is relevant to a variety of scientific and applied disciplines, it is imperative to have a complete and accurate account of how and where male and female faces differ. We apply a comprehensive facial phenotyping strategy to a large set of existing 3D facial surface images. We investigate facial sexual dimorphism in terms of size, shape, and shape variance. We also assess the ability to correctly assign sex based on shape, both for the whole face and for subregions. We applied a predefined data-driven segmentation to partition the 3D facial surfaces of 2446 adults into 63 hierarchically linked regions, ranging from global (whole face) to highly localized subparts. Each facial region was then analyzed with spatially dense geometric morphometrics. To describe the major modes of shape variation, principal components analysis was applied to the Procrustes aligned 3D points comprising each of the 63 facial regions. Both nonparametric and permutation-based statistics were then used to quantify the facial size and shape differences and visualizations were generated. Males were significantly larger than females for all 63 facial regions. Statistically significant sex differences in shape were also seen in all regions and the effects tended to be more pronounced for the upper lip and forehead, with more subtle changes emerging as the facial regions became more granular. Males also showed greater levels of shape variance, with the largest effect observed for the central forehead. Classification accuracy was highest for the full face (97%), while most facial regions showed an accuracy of 75% or greater. In summary, sex differences in both size and shape were present across every part of the face. By breaking the face into subparts, some shape differences emerged that were not apparent when analyzing the face as a whole. The increase in facial shape variance suggests possible evolutionary origins and may offer insights for understanding congenital facial malformations. Our classification results indicate that a high degree of accuracy is possible with only parts of the face, which may have implications for biometrics applications.

Food insecurity and consumption of cariogenic foods in mothers and their two-year-old children in Appalachia.

OBJECTIVES: To describe the association between household food insecurity and intake of cariogenic foods that increase risk of dental caries. METHODS: Cross-sectional analysis of 842 mothers in Appalachia and their children participating in the Center for Oral Health Research Cohort 2 between 2011 and 2017 when their children were ~ 24 months of age. Mothers completed a telephone interview regarding cariogenic food consumption and food insecurity. Associations between food insecurity and daily food intake were adjusted for education, income, state residence, and daily snacking. RESULTS: After adjustment for household income, state residence, daily snacking, and maternal education, mothers from moderately/severely food insecure households drank on average ½ more sugar-sweetened beverage servings per day (p = 0.005) and children drank almost 1/3 servings more (p = 0.006). Further, mothers and children from moderately/severely food insecure households had lower, but not statistically significant, daily average consumption of vegetables (mothers: 1/5 less of a vegetable serving per day, children: ~1/10 less) and fruits (mothers: 1/5 less of a fruit serving per day, children: ~ 1/10 les) and elevated consumption of sweets (mothers: ~ 1/25 more sweet servings per day, children: ~ 2/25 more); differences based on state residence were noted. CONCLUSIONS: Food insecurity is associated with higher consumption of foods that increase risk of dental caries, but this association is modified by maternal education, income, and state residence. Food insecurity, and its socioeconomic determinants, should be considered when designing and implementing interventions to prevent dental caries.

Early Childhood Diet in Relation to Toddler Nighttime Sleep Duration Trajectories.

The objective of this study was to evaluate whether dietary habits at age 2 associate with sleep duration trajectories through age 5 in children from north and central Appalachia. A total of 559 children from the Center for Oral Health Research in Appalachia (COHRA) cohort 2 were followed via caregiver phone interviews up to six times between ages 2 and 5. Exposures included data from the year 2 interview: sleep habits, household and demographic characteristics, meal patterns and consumption frequencies of fruits, vegetables, water, juice, milk, and soda. Sleep duration trajectories were identified using group-based trajectory models from ages 2 to 5. Three distinct nightly sleep duration trajectories were identified: short, increasing duration (4.5% of the study population); steady, 9 h of sleep (37.3%); and longer, slightly decreasing sleep duration (58.2%). Using multinomial logistic models that accounted for confounders, children with consistent meal patterns (i.e., meals and snacks at same time every day) and with higher fruit and vegetable consumption were more likely to follow the longer duration sleep trajectory compared to the steady sleep trajectory. In contrast, children who drank milk more frequently at age 2 were less likely to be in the longer duration sleep trajectory than the steady sleep trajectory.

Bent pinkies: Quantifying fifth finger clinodactyly in a sample of U.S. adults.

Mild curvature of the fifth finger (or clinodactyly) is a relatively common trait. While severe forms can cause functional impairment and are a feature of certain congenital syndromes, mild clinodactyly is considered a minor morphological variant. Despite exhibiting continuous variation, clinodactyly is rarely treated as a quantitative trait. Consequently, the degree of fifth finger curvature in the general population and the factors that impact this curvature are not well understood. In the present study, we measured fifth finger curvature in a sample of 1,295 U.S. adults and investigated the role of sex, age and body size. We found that clinodactyly exhibited a non-normal distribution. All participants displayed some degree of curvature, but it tended to be slight with an overall mean of 3.68 degrees (median: 3.58 degrees). In only 0.8% of cases did the curvature exceed the nominal 10-degree threshold for clinically meaningful clinodactyly. We did not find statically significant sex differences. Further, there was no meaningful relationship with height and only a weak positive relationship with age. We found that clinodactyly showed asymmetry; the curvature was greater on the left than on the right fifth finger (p < 2.2e-16), but this was not influenced by sex, age, or height. These results suggest the possibility that the kind of ubiquitous mild clinodactyly observed in the general population may be etiologically distinct from more rare and severe forms of the condition.

Racism in oral healthcare settings: Implications for dental care-related fear/anxiety and utilization among Black/African American women in Appalachia.

OBJECTIVE: To explore the association of racism in oral healthcare settings and dental care-related fear/anxiety with dental utilization among Black/African American women in Appalachia. METHODS: We analyzed self-report measures of racism in oral healthcare settings, dental care-related anxiety and fear, recency of a dental visit, and demographic information from 268 pregnant women participating in the Center for Oral Health Research in Appalachia (COHRA) SMILE cohort. All participants self-identified as African American or Black and resided in Appalachia (i.e., either West Virginia or Pittsburgh, PA). RESULTS: Over one-third of the participants reported at least one instance of racism in oral healthcare settings, with "not being listened to" due to their race or color as the most frequent issue (24.4%). Clinically significant levels of dental care-related anxiety and fear were reported by 14.3% of the sample. A mediational model demonstrated that the experience of racism in oral healthcare settings was a significant predictor of dental fear/anxiety, and that dental fear/anxiety was a significant predictor of dental utilization. There was a significant relationship between racism in oral healthcare settings and dental utilization only when mediated by the presence of dental care-related fear and anxiety. CONCLUSIONS: Together, experiences of racism in oral healthcare settings and dental care-related fear/anxiety are predictive of decreased dental utilization for Black/African American women living in Appalachia. This study provides insight into racism in oral healthcare settings as a social determinant of dental anxiety/fear and inequities in dental utilization.

Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morphology.

Variations in the form of the human face, which plays a role in our individual identities and societal interactions, have fascinated scientists and artists alike. Here, we review our current understanding of the genetics underlying variation in craniofacial morphology and disease-associated dysmorphology, synthesizing decades of progress on Mendelian syndromes in addition to more recent results from genome-wide association studies of human facial shape and disease risk. We also discuss the various approaches used to phenotype and quantify facial shape, which are of particular importance due to the complex, multipartite nature of the craniofacial form. We close by discussing how experimental studies have contributed and will further contribute to our understanding of human genetic variation and then proposing future directions and applications for the field.

Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes.

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E-05) within previously confirmed OFC loci-PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster-were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.

Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

Genome-wide Interaction Study Implicates VGLL2 and Alcohol Exposure and PRL and Smoking in Orofacial Cleft Risk.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting approximately 1 in 700 births. NSCL/P has complex etiology including several known genes and environmental factors; however, known genetic risk variants only account for a small fraction of the heritability of NSCL/P. It is commonly suggested that gene-by-environment (G×E) interactions may help explain some of the "missing" heritability of NSCL/P. We conducted a genome-wide G×E interaction study in cases and controls of European ancestry with three common maternal exposures during pregnancy: alcohol, smoking, and vitamin use using a two-stage design. After selecting 127 loci with suggestive 2df tests for gene and G x E effects, 40 loci showed significant G x E effects after correcting for multiple tests. Notable interactions included SNPs of 6q22 near VGLL2 with alcohol and 6p22.3 near PRL with smoking. These interactions could provide new insights into the etiology of CL/P and new opportunities to modify risk through behavioral changes.