A post GWAS association study of SNPs associated with cleft lip with or without cleft palate in submucous cleft palate

Reiter, Rudolf; Brosch, S.; Goebel, Ingrid; Ludwig, Kerstin U.; Pickhard, Anja; Högel, Josef; Schlömer, Guido; Mangold, Elisabeth; Kubisch, Christian; Borck, Guntram

doi:10.1002/ajmg.a.36891

Cited by 10 publications

(9 citation statements)

References 21 publications

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“…To increase the size of this CLP soft group we reached out to other clinical nsCL/P cohorts and identified eight patients meeting the CLP soft criteria in a Dutch nsCL/P sample [ 56 ]: Six of these patients were part of the EuroCran cohort while two patients were drawn from an independent Dutch sample [ 57 ]. In addition, rs1258763 was genotyped in: (i) 45 patients with a cleft of the soft palate only (CPO soft ), which is an orofacial clefting subform with a different genetic background; and (ii) 115 patients from a cohort of submucous cleft palate patients (CPO submuc ) [ 58 ].…”

Section: Methodsmentioning

confidence: 99%

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

et al. 2016

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Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

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Section: Methodsmentioning

confidence: 99%

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

et al. 2016

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“…11 Additional CL/P SNPs were tested for association with submucous CP, but again were not significantly associated. 12 However, other candidate gene studies have shown association with both CL/P and CP including a SNP within microRNA-140 (MIM: 611894) 13 and SNPs near FOXE1 (MIM: 602617). 14 Overall there seems to be little overlap between loci associated with CL/P and the few loci associated with CP to date, supporting the notion that CL/P and CP largely have distinct genetic etiologies.…”

Section: Introductionmentioning

confidence: 99%

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

Leslie

Liu

Carlson

et al. 2016

The American Journal of Human Genetics

141

194

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Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.

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“…Four articles [13,20,21,22] reported polymorphisms in Asians, three [23,24,25] in “Caucasians”, two [26,27] in mixed, and one [28] in African ethnicities. The source of controls was hospital-based in four [13,21,23,24] and population-based in four other articles [20,25,26,27]. All studies reported rs13041247 MAFB polymorphism involving 3082 NSCL/P patients and 4104 controls.…”

Section: Resultsmentioning

confidence: 99%

Polymorphic Variants of V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (rs13041247 and rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis

Imani

López‐Jornet

Pons-Fuster

et al. 2019

IJERPH

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Background: Non-syndromic cleft lip/palate (NSCL/P) has an etiology, including both genetic and environmental factors. Herein, we evaluated the association of rs13041247 and rs11696257 v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) polymorphisms with the risk of NSCL/P in a meta-analysis. Methods: The PubMed/Medline, Scopus, Cochrane Library, Web of Science, and HuGE Navigator databases were systematically searched to retrieve relevant articles published up to January 2019. The Newcastle–Ottawa scale was applied for quality evaluation of retrieved articles. The 95% confidence interval (CI) and crude odds ratio (OR) were calculated for each study using the Review Manager 5.3 software to show the association between MAFB polymorphisms and risk of NSCL/P. The comprehensive meta-analysis 2.0 software was used to calculate the publication bias. In addition, sensitivity analysis was carried out to show the stability of results. Results: Of 102 articles retrieved from the databases, 10 articles were analyzed in this meta-analysis. Ten articles, including eleven studies reporting rs13041247 MAFB polymorphism, included 3082 NSCL/P patients and 4104 controls. Three studies that reported rs11696257 MAFB polymorphism involved 845 NSCL/P patients and 927 controls. The rs11696257 MAFB polymorphism was not associated with the risk of NSCL/P, but the CC and TC genotypes of rs13041247 polymorphism were associated with the risk of NSCL/P. Nevertheless, the C allele and CC and TC genotypes were associated with a significant decline in the risk of NSCL/P in population-based studies. Conclusions: The results of this meta-analysis demonstrated that the risk of NSCL/P was related to rs13041247 polymorphism, not rs11696257 MAFB polymorphism. Well-designed studies are required to assess the interaction of MAFB and other genes with environmental factors in different ethnic groups.

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A post GWAS association study of SNPs associated with cleft lip with or without cleft palate in submucous cleft palate

Cited by 10 publications

References 21 publications

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

Polymorphic Variants of V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (rs13041247 and rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis

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