Association between genes on chromosome 4p16 and non-syndromic oral clefts in four populations.
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ABSTRACT:
SUBMITTER: Ingersoll RG
PROVIDER: S-EPMC2874614 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts.
| S-EPMC3327729 | biostudies-literature
Project description:ObjectiveIn this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction.MethodsWe conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment in teraction using trio package in R software. The threshold of significance level was set as 3.47×10-4 using Bonferroni correction.ResultsA total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P < 3.47×10-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios.ConclusionThough this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.
| S-EPMC7653429 | biostudies-literature
Project description:Recent work suggests that multiple genes and several environmental risk factors influence risk for non-syndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously.We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case-parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes.Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here.This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case-parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.
| S-EPMC2564555 | biostudies-literature
Project description:ObjectiveTo explore the association between SPRY gene family and the risk of non-syndromic oral clefts among Chinese populations, in respect of single nucleotide polymorphisms (SNPs) association and parent-of-origin effects.MethodsBased on case-parent design, this study used the data of SPRY gene family in a next generation sequencing study of 183 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios (549 participants) recruited from 2016 to 2018, to analyze the effects of SNP association and parent-of-origin. The sequencing study adopted a two-stage design. In the first stage, whole exome sequencing was conducted among 24 NSCL/P trios with family history to explore potential signals. Then in the second stage, another 159 NSCL/P trios were used as validation samples to verify the signals found in the first stage. The data of general information, disease features and parental environmental exposures for participants were collected through questionnaires. Blood samples were collected from each participant for DNA extraction and sequencing. Transmission disequilibrium tests (TDT) were conducted to test for the association between SNPs and NSCL/P, while Z score tests were applied to analyze parent-of-origin effects. The analyses were performed using Plink (v1.07). TRIO package in R (v3.5.1). Besides, famSKAT analyses were conducted in the first stage to combine the effect of SNPs located on the same gene, using famSKAT package in R(V3.5.1). Bonferroni method was adopted to correct multiple tests in the second stage.ResultsTwenty-two SNPs in SPRY gene family were included for analyses after the quality control process in the first stage. Based on the variants annotation, functional prediction and statistical analysis, rs1298215244 (SPRY1) and rs504122 (SPRY2) were included in the second verification stage. TDTs in the verification stage revealed that rs1298215244: T>C, rs504122: G>C and rs504122: G>T were associated with the risk of NSCL/P after Bonferroni corrections, where rs504122: G>T was a rare variation. Although the test for parent-of-origin effect of rs1298215244: T>C reached nominal significance level, no SNP showed significant association with NSCL/P through parent-of-origin effect after Bonferroni corrections.ConclusionThis study found that SNPs (including both common and rare variants) among the SPRY gene family were associated with the risk of NSCL/P among Chinese populations. This study failed to detect parent-of-origin effects among the SPRY gene family.
| S-EPMC7439039 | biostudies-literature
Project description:Maternal periconceptional folic acid supplementation (FAS) has been documented to be associated with decreased risk of nonsyndromic oral clefts (NsOC). However, the results remain inconclusive. In this population-based case-control study of 807 singletons affected by NsOC and 8070 healthy neonates who were born between October 2010 and September 2015 in Chengdu, China, we examined the association of maternal FAS with the risk of nonsyndromic cleft lip with or without cleft palate (NsCL/P), and cleft palate (NsCP). Unconditional logistic regression analysis was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidential intervals (CI). Significant associations were found between maternal periconceptional FAS and decreased risk of NsCL/P (aOR = 0.41, 95% CI 0.33-0.51). This protective effect was also detected for NsCL (aOR = 0.42, 95% CI 0.30-0.58) and NsCLP (aOR = 0.41, 95% CI 0.31-0.54). Both maternal FAS started before and after the last menstrual period (LMP) were inversely associated with NsCL/P (before LMP, aOR = 0.43, 95% CI 0.33-0.56; after LMP, aOR = 0.41, 95% CI 0.33-0.51). The association between NsCP and maternal FAS initiating before LMP was also found (aOR = 0.52, 95% CI 0.30-0.90). The findings suggest that maternal periconceptional FAS can reduce the risk of each subtype of NsCL/P in offspring, while the potential effect on NsCP needs further investigations.
| S-EPMC8192944 | biostudies-literature
Project description:The aim of this study was to investigate the risk of psychiatric diagnoses in individuals with non-syndromic oral clefts (OC) compared with individuals without OC, including ages from 1 to 76 years.Linking four Danish nationwide registers, we investigated the risk of psychiatric diagnoses at Danish psychiatric hospitals during the period 1969-2012 for individuals born with non-syndromic OC in Denmark 1936-2009 compared with a cohort of 10 individuals without OC per individual with OC, matched by sex and birth year. The sample included 8,568 individuals with OC, observed for 247,821 person-years, and 85,653 individuals without OC followed for 2,501,129 person-years.A total of 953 (11.1%) of the individuals with OC (9.6% for cleft lip (CL), 10.8% for cleft lip and palate (CLP) and 13.1% for cleft palate (CP)) and 8,117 (9.5%) in the comparison group had at least one psychiatric diagnosis. Cox proportional hazard regression model revealed that individuals with OC had significantly higher risk of a psychiatric diagnosis (hazard ratio (HR) = 1.19, 95% CI: 1.12-1.28). When examining cleft type, no difference was found for CL (HR = 1.03, 95% CI: 0.90-1.17), but CLP was associated with a small increased risk (HR = 1.13, 95% CI: 1.01-1.26), whereas individuals with CP had the largest increased risk (HR = 1.45, 95% CI: 1.30-1.62). The largest differences were found in schizophrenia-like disorders, mental retardation and pervasive developmental disorders, but we found no increased risk of mood disorders and anxiety-related disorders.Individuals with non-syndromic OC had significantly higher risk of psychiatric diagnoses compared with individuals without OC. However, the elevated risk was observed for individuals with CLP and CP but not for individuals with CL and the absolute risk increase was modest.
| S-EPMC4880322 | biostudies-other
Project description:To date, the involvement of various genetic markers in the aetiopathogenesis of non-syndromic orofacial cleft (nsOFC) has been extensively studied. In the present study, we focused on studies performed on populations of European ancestry to systematically review the available literature to define relevant genetic risk factors for nsOFC. Eligible studies were obtained by searching Ovid Medline and Ovid Embase. We gathered the genetic markers from population-based case-control studies on nsOFC, and conducted meta-analysis on the repeatedly reported markers. Whenever possible, we performed stratified analysis based on different nsOFC phenotypes, using allelic, dominant, recessive and overdominant genetic models. Effect sizes were expressed as pooled odds ratios (ORs) with 95% confidence intervals (CIs), and p ≤ 0.05 were considered statistically significant. A total of 84 studies were eligible for this systematic review, with > 700 markers included. Of these, 43 studies were included in the meta-analysis. We analysed 47 genetic variants in 30 genes/loci, which resulted in 226 forest plots. There were statistically significant associations between at least one of the nsOFC phenotypes and 19 genetic variants in 13 genes/loci. These data suggest that IRF6, GRHL3, 8q24, VAX1, TGFA, FOXE1, ABCA4, NOG, GREM1, AXIN2, DVL2, WNT3A and WNT5A have high potential as biomarkers of nsOFC in populations of European descent. Although other meta-analyses that included European samples have been performed on a limited number of genetic variants, this study represents the first meta-analysis of all genetic markers that have been studied in connection with nsOFC in populations of European ancestry.
| S-EPMC8786890 | biostudies-literature
Project description:Non syndromic orofacial clefts specifically non-syndromic cleft lip/palate are one of the most common craniofacial malformation among birth defects in human having multifactorial etiology with an incidence of 1:700/1000. On the basis of association with other congenital malformations or their presence as isolated anomaly, OFC can be classified as syndromic (30%) and nonsyndromic (70%) respectively. The major cause of disease demonstrates complex interplay between genetic and environmental factors. The pathogenic mechanism of underlying factors have been provided by different genetic studies on large-scale with significant recent advances in genotyping technologies usually based on linkage or genome wide association studies (GWAS). On the basis of recent studies, new tools to identify causative genes involved in NSCL/P reported approximately more than 30 genetic risk loci that are responsible for pathogenesis of facial deformation. Despite these findings, it is still uncertain that how much of variance in NSCL/P predisposing factors can be explain by identified risk loci, as they all together accounts for only 20%-25% of NSCL/P heritability. So there is need of further findings about the problem of rare low frequency coding variants and other missing responsive factors or genetic modifiers. This review will described those potential genes and loci reported in different studies whose involvement in pathogenesis of nonsyndromic OFC has wide scientific evidence.
| S-EPMC6921104 | biostudies-literature
Project description:OFCs (orofacial clefts) are among the most frequent congenital defects, but their etiology has yet to be clarified. OFCs affect different structures and functions with social, psychological and economic implications in children and their families. Identifying modifiable risk factors is mandatory to prevent the occurrence of non-syndromic OFCs (NSOFCs). PubMed, Cochrane Library, Scopus and Web of Science were searched from 1 January 2012 to 25 May 2022 and a total of 7668 publications were identified. Studies focusing on the risk factors of NSOFCs were selected, leading to 62 case-control and randomized clinical trials. Risk factors were categorized into non-modifiable and modifiable. The first group includes genetic polymorphisms, gender of the newborn, ethnicity, and familiarity. Within the second group, risk factors that can only be modified before conception (consanguinity, parental age at conception, socio-economical and educational level, area of residency and climate), and risk factors modifiable before and after conception (weight, nutritional state, acute and chronic diseases, psychophysical stress, licit and illicit drugs, alcohol, smoke, pollutants and contaminants) have been distinguished. This study provides a wide overview of the risk factors of NSOFCs, focusing on modifiable ones, to suggest new perspectives in education, prevention, medical interventions and clinical research.
| S-EPMC9777067 | biostudies-literature
Project description:Copy number variants have been associated with intellectual disability, multiple congenital anomalies and craniofacial disorders. It has been reported that microduplication of 15q13.3 is associated with autism, cognitive impairment, seizures, and attention-deficit hyperactivity disorder. Here, the author identified microduplications in the 15q13.3 region in 4 cases from 3 Chinese families using chromosomal microarray analysis-single nucleotide polymorphism array (CMA-SNP). These 4 cases include 2 fetuses from 2 unrelated families and a father and a daughter from a third family. The identified microduplications of 15q13.3 are approximately 400 kb in size, encompassing just 1 gene, cholinergic receptor, neuronal nicotinic, alpha polypeptide 7 (CHRNA7). Three-fourths of the probands exhibit oral clefts, which has not been previously reported in cases with this duplication genotype. Therefore, in this study, the author describes for the first time the common feature of oral clefts in patients carrying a microduplication of 15q13.3 encompassing the CHRNA7 gene, which sheds light on the correlation between CHRNA7 and cleft palate.
| S-EPMC5417031 | biostudies-literature