Genome‐wide interaction studies identify sex‐specific risk alleles for nonsyndromic orofacial clefts

Carlson, Jenna C.; Nidey, Nichole; Butali, Azeez; Buxó, Carmen J.; Christensen, Kaare; Deleyiannis, Frederic; Hecht, Jacqueline; Field, L. Leigh; Moreno‐Uribe, Lina; Orioli, Iêda M.; Poletta, Fernando A.; Padilla, Carmencita D.; Vieira, Alexandre R.; Weinberg, Seth M.; Wehby, George L.; Feingold, Eleanor; Murray, Jeffrey C.; Marazita, Mary L.; Leslie, Elizabeth J.

doi:10.1002/gepi.22158

Cited by 18 publications

(13 citation statements)

References 47 publications

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“…We searched the GWAS Catalog and found five studies based on CPO-related GWAS [12, 15, 38–40]. These studies did not discover IRF6 locus in CPO perhaps because of 1) a small sample size in the discovery stage and 2) a large degree of population mixture in the discovery stage.…”

Section: Discussionmentioning

confidence: 99%

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

et al. 2019

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Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10−8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

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Section: Discussionmentioning

confidence: 99%

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

et al. 2019

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“…An exception to this is, for example, the article by Burdi and Silvey (1969) in which the shifting of the female palatal shelves from vertical to horizontal occurs approximately half a week later than in the male embryos increasing the risk for CP and possibly explaining the female preponderance of CP. According to Carlson et al (2018), genetic variations may contribute to the delay.…”

Section: Discussionmentioning

confidence: 99%

Embryologically Based Classification Specifies Gender Differences in the Prevalence of Orofacial Cleft Subphenotypes

Pool

Lek

Jong

et al. 2020

The Cleft Palate Craniofacial Journal

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Background: A recently published validated classification system divides all orofacial cleft (OFC) subphenotypes into groups based on underlying developmental mechanisms, that is, fusion and differentiation, and their timing, that is, early and late periods, in embryogenesis of the primary and secondary palates. Aims: The aim of our study was to define gender differences in prevalence for all subphenotypes in newborns with OFC in the Netherlands. Methods: This was a retrospective cross-sectional study on children with OFC born from 2006 to 2016. Clefts were classified in early (E-), late (L-), and early/late (EL-) embryonic periods, in primary (P-), secondary (S-), and primary/secondary (PS-) palates, and further divided into fusion (F-), differentiation (D-), and fusion/differentiation (FD-) defects, respectively. Results: A total of 2089 OFC children were analyzed (1311 males and 778 females). Orofacial cleft subphenotypes in females occurred significantly more frequent in the L-period compared to males (66% vs 55%, P = .000), whereas clefts in males occurred significantly more in the EL-periods (40% vs 27%, P = .000). Females had significantly more S-palatal clefts (42% vs 23%, P = .000), while males had significantly more PS-palatal clefts (44% vs 30%, P = .000). Furthermore, the clefts in females were significantly more frequent the result of an F-defect (60% vs 52%, P = .000). Conclusions: Orofacial cleft in females mainly occur in the L-period are mostly S-palatal clefts, and are usually the result of an F-defect. Orofacial cleft in males more commonly occur in the EL-periods, are therefore more often combined PS-palatal clefts, and are more frequent D- and FD-defects.

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“…To conduct a more detailed investigation, we subdivided the fusion stage into the early fusion and late fusion stage in miniature pigs, as most CLP occurs in the fusing stage [2,6,14]. Genome information about normal palate development is limited, while most genome analyses of palate development have focused on the genetics of CLP [30,31,32,33]. Mice were used as models, with differential gene expression identified for only some pathways, such as the TGFβ and WNT signaling pathways, which were previously a focus [17,18].…”

Section: Discussionmentioning

confidence: 99%

Dynamic mRNA Expression Analysis of the Secondary Palatal Morphogenesis in Miniature Pigs

Liu

Chen

Dong

et al. 2019

IJMS

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Normal mammalian palatogenesis is a complex process that requires the occurrence of a tightly regulated series of specific and sequentially regulated cellular events. Cleft lip/palate (CLP), the most frequent craniofacial malformation birth defects, may occur if any of these events undergo abnormal interference. Such defects not only affect the patients, but also pose a financial risk for the families. In our recent study, the miniature pig was shown to be a valuable alternative large animal model for exploring human palate development by histology. However, few reports exist in the literature to document gene expression and function during swine palatogenesis. To better understand the genetic regulation of palate development, an mRNA expression profiling analysis was performed on miniature pigs, Sus scrofa. Five key developmental stages of miniature pigs from embryonic days (E) 30–50 were selected for transcriptome sequencing. Gene expression profiles in different palate development stages of miniature pigs were identified. Nine hundred twenty significant differentially expressed genes were identified, and the functional characteristics of these genes were determined by gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Some of these genes were associated with HH (hedgehog), WNT (wingless-type mouse mammary tumor virus integration site family), and MAPK (mitogen-activated protein kinase) signaling, etc., which were shown in the literature to affect palate development, while some genes, such as HIP (hedgehog interacting protein), WNT16, MAPK10, and LAMC2 (laminin subunit gamma 2), were additions to the current understanding of palate development. The present study provided a comprehensive analysis for understanding the dynamic gene regulation during palate development and provided potential ideas and resources to further study normal palate development and the etiology of cleft palate.

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Genome‐wide interaction studies identify sex‐specific risk alleles for nonsyndromic orofacial clefts

Cited by 18 publications

References 47 publications

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

Embryologically Based Classification Specifies Gender Differences in the Prevalence of Orofacial Cleft Subphenotypes

Dynamic mRNA Expression Analysis of the Secondary Palatal Morphogenesis in Miniature Pigs

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