Joint Testing of Genotypic and Gene-Environment Interaction Identified Novel Association for BMP4 with Non-Syndromic CL/P in an Asian Population Using Data from an International Cleft Consortium

Chen, Qianqian; Wang, Hong; Schwender, Holger; Zhang, Tianxiao; Hetmanski, Jacqueline B.; Chou, Yah Huei Wu; Ye, Xiaoqian; Yeow, Vincent; Chong, Samuel S.; Zhang, Bo; Jabs, Ethylin Wang; Parker, Margaret M.; Scott, Alan F.; Beaty, Terri H.

doi:10.1371/journal.pone.0109038

Cited by 20 publications

(15 citation statements)

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“…Liu et al, 2005] and association studies [e.g. Chen et al, 2014]. Furthermore, a gene sequencing study [Suzuki et al, 2009] demonstrated that rare BMP4 coding mutations were enriched in CLP cases at similar frequencies to those shown here.…”

Section: Folate Pathway Variation: Methionine Cycle Genessupporting

confidence: 76%

Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate

Marini

Asrani

Yang

et al. 2019

Preprint

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Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 non-malformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = 0.03), including multiple case occurrences of a rare frameshift mutation (K400fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.

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Section: Folate Pathway Variation: Methionine Cycle Genessupporting

confidence: 76%

Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate

Marini

Asrani

Yang

et al. 2019

Preprint

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“…Five of our 75 candidate loci with abnormal methylation being BMP4 , ENAH , GALNT2 , and NRP2 and one CpG in a locus without an annotated gene seem to be highly significantly influenced by maternal smoking. Bone morphogenetic protein 4 ( BMP4 ) is of special interest as it is involved in craniofacial development and an important candidate gene for cleft palate defects [ 27 ]. However, BMP4 has not yet been implicated directly in lumbosacral MMC.…”

Section: Discussionmentioning

confidence: 99%

Methylome analysis for spina bifida shows SOX18 hypomethylation as a risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development

et al. 2016

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BackgroundNeural tube defects (NTDs) are severe congenital malformations that arise from failure of neurulation during early embryonic development. The molecular basis underlying most human NTDs still remains largely unknown. Based on the hypothesis that folic acid prevents NTDs by stimulating methylation reactions, DNA methylation changes could play a role in NTDs. We performed a methylome analysis for patients with myelomeningocele (MMC). Using a candidate CpG analysis for HOX genes, a significant association between HOXB7 hypomethylation and MMC was found.MethodsIn the current study, we analyzed leukocyte methylome data of ten patients with MMC and six controls using Illumina Methylation Analyzer and WateRmelon R-packages and performed validation studies using larger MMC and control cohorts with Sequenom EpiTYPER.ResultsThe methylome analysis showed 75 CpGs in 45 genes that are significantly differentially methylated in MMC patients. CpG-specific methylation differences were next replicated for the top six candidate genes ABAT, CNTNAP1, SLC1A6, SNED1, SOX18, and TEPP but only for the SOX18 locus a significant overall hypomethylation was observed (P value = 0.0003). Chemically induced DNA demethylation in HEK cells resulted in SOX18 hypomethylation and increased expression. Injection of sox18 mRNA in zebrafish resulted in abnormal neural tube formation. Quantification of DNA methylation for the SOX18 locus was also determined for five families where parents had normal methylation values compared to significant lower values for both the MMC as their non-affected child. SOX18 methylation studies were performed for a MMC patient with a paternally inherited chromosomal deletion that includes BMP4. The patient showed extreme SOX18 hypomethylation similar to his healthy mother while his father had normal methylation values.ConclusionsThis is the first genome-wide methylation study in leukocytes for patients with NTDs. We report SOX18 as a novel MMC risk gene but our findings also suggest that SOX18 hypomethylation must interplay with environmental and (epi)genetic factors to cause NTDs. Further studies are needed that combine methylome data with next-generation sequencing approaches to unravel NTD etiology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0272-8) contains supplementary material, which is available to authorized users.

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“…RCAS::PI15 upregulated several of these genes that increase the risk of developing human non-syndromic clefts including TP63 (Barbaro et al, 2012;Clements et al, 2010;Kantaputra et al, 2011a), BMP4 (Chen et al, 2014;Kempa et al, 2014;Suzuki et al, 2009;Thomason et al, 2008) and FOXE1 (Ludwig et al, 2014). TBX22 mutations cause cleft palate only in humans (Fu et al, 2015;Kantaputra et al, 2011b;Pauws et al, 2009).…”

Section: Pi15 and The Relationship To Orofacial Cleftingmentioning

confidence: 99%

“…TBX22 mutations cause cleft palate only in humans (Fu et al, 2015;Kantaputra et al, 2011b;Pauws et al, 2009). Most of the mutations in the aforementioned clefting genes are missense mutations with unknown functional consequences (Barbaro et al, 2012;Clements et al, 2010;Kantaputra et al, 2011a;Kantaputra et al, 2011b;Kempa et al, 2014;Suzuki et al, 2009) or polymorphisms associated with clefting (Chen et al, 2014;Ludwig et al, 2014). Thus it is valid to study gain-of-function in the chicken system as a complement to loss of function in the mouse model.…”

Section: Pi15 and The Relationship To Orofacial Cleftingmentioning

confidence: 99%

Identification and functional analysis of novel facial patterning genes in the duplicated beak chicken embryo

Nimmagadda

Buchtová

et al. 2015

Developmental Biology

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Cranial neural crest cells form the majority of the facial skeleton. However exactly when the pattering information and hence jaw identity is established is not clear. We know that premigratory neural crest cells contain a limited amount of information about the lower jaw but the upper jaw and facial midline are specified later by local tissue interactions. The environmental signals leading to frontonasal identity have been explored by our group in the past. Altering the levels of two signaling pathways (Bone Morphogenetic Protein) and retinoic acid (RA) in the chicken embryo creates a duplicated midline on the side of the upper beak complete with egg tooth in place of maxillary derivatives (Lee et al., 2001). Here we analyze the transcriptome 16 h after bead placement in order to identify potential mediators of the identity change in the maxillary prominence. The gene list included RA, BMP and WNT signaling pathway genes as well as transcription factors expressed in craniofacial development. There was also cross talk between Noggin and RA such that Noggin activated the RA pathway. We also observed expression changes in several poorly characterized genes including the upregulation of Peptidase Inhibitor-15 (PI15). We tested the functional effects of PI15 overexpression with a retroviral misexpression strategy. PI15 virus induced a cleft beak analogous to human cleft lip. We next asked whether PI15 effects were mediated by changes in expression of major clefting genes and genes in the retinoid signaling pathway. Expression of TP63, TBX22, BMP4 and FOXE1, all human clefting genes, were upregulated. In addition, ALDH1A2, ALDH1A3 and RA target, RARβ were increased while the degradation enzyme CYP26A1 was decreased. Together these changes were consistent with activation of the RA pathway. Furthermore, PI15 retrovirus injected into the face was able to replace RA and synergize with Noggin to induce beak transformations. We conclude that the microarrays have generated a rich dataset containing genes with important roles in facial morphogenesis. Moreover, one of these facial genes, PI15 is a putative clefting gene and is in a positive feedback loop with RA.

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Joint Testing of Genotypic and Gene-Environment Interaction Identified Novel Association for BMP4 with Non-Syndromic CL/P in an Asian Population Using Data from an International Cleft Consortium

Cited by 20 publications

References 42 publications

Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate

Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate

Methylome analysis for spina bifida shows SOX18 hypomethylation as a risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development

Identification and functional analysis of novel facial patterning genes in the duplicated beak chicken embryo

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