Analysis of susceptibility loci for nonsyndromic orofacial clefting in a European trio sample

Böhmer, Anne C.; Mangold, Elisabeth; Tessmann, Peter; Mossey, Peter; Steegers‐Theunissen, R.P.M.; Lindemans, Jan; Bouwman-Both, Marieke; Rubini, Michele; Franceschelli, Paola; Aiello, Vincenzo; Peterlin, Borut; Molloy, Anne M.; Nöthen, Markus M.; Knapp, Michael; Ludwig, Kerstin U.

doi:10.1002/ajmg.a.36141

Cited by 24 publications

(24 citation statements)

References 17 publications

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“…Our study is the first to report differential effects of ABCA4-ARHGAP29 on CLP and CLO and opposite NOG1 effects on CLO and CPO, including the significant reduction in CPO risk. The lack of significant associations of other loci with isolated CPO is consistent with prior studies (Beaty et al 2011; Böhmer et al 2013; Leslie et al 2017; Ludwig et al 2017) and studies of familial recurrence suggesting a distinct etiology for CPO in many, if not most, cases (Sivertsen et al 2008; Grosen et al 2010). Among all examined loci, 8q24 (rs987525) had the strongest effects on isolated CLO and CLP.…”

Section: Discussionsupporting

confidence: 86%

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

et al. 2017

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Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the Reprints and permissions: sagepub.com/journalsPermissions.nav Corresponding Author: L.M. Moreno Uribe, Orthodontics-Dows Institute, University of Iowa, 401 DSB, Iowa City, IA 52242, USA. lina-moreno@uiowa.edu. * Authors contributing equally as senior authors. Author ContributionsL.M. Moreno Uribe, G.L. Wehby, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; T. Fomina, H.K. Gjessing, M. Gjerdevik, contributed to data analysis, critically revised the manuscript; R.G. Munger, P.A. Romitti, M.M. Jenkins, K. Christensen, contributed to data acquisition, critically revised the manuscript; A.J. Wilcox, J.C. Murray, contributed to data acquisition and interpretation, critically revised the manuscript; R.T. Lie, contributed to conception, design, data acquisition, analysis, and interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.A supplemental appendix to this article is available online. HHS Public AccessAuthor manuscript J Dent Res. Author manuscript; available in PMC 2017 October 01. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a motherchild dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent.

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Section: Discussionsupporting

confidence: 86%

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

et al. 2017

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“…Further confirmation of the role of PAX7 in the etiology of orofacial clefts was provided by imputation analysis, which identified additional risk variants for nsCL/P. The top‐ranked imputed SNP identified in our study (rs742071) is an already known risk SNP, in which association with orofacial clefts was confirmed in various populations (Beaty et al, , ; Böhmer et al, ; Gowans et al, ; Leslie et al, ; Ludwig et al, ). In the combined European/Asian meta‐analysis for nsCL/P conducted by Ludwig et al (), the rs742071 reached even the genome‐wide significance threshold ( p ‐value < 5 × E−08).…”

Section: Discussionsupporting

confidence: 63%

“…In addition, common nucleotide variants of this gene have been shown to correlate with the risk of non‐syndromic cleft lip with or without cleft palate (nsCL/P, OMIM %119530) (Lee, Park, Kim, & Baek, ). The increased risk of nsCL/P, as well as craniofacial skeletal variation among patients with malocclusion, has also been found to be associated with common variants of PAX5 and PAX7 (Beaty et al, , ; Böhmer et al, ; Butali et al, ; da Fontoura et al, ; Gowans et al, ; Leslie et al, ; Ludwig et al, ; Sull et al, ). In the meta‐analyses of genome‐wide association studies (GWASs) for nsCL/P, the results for the PAX7 variants reached the genome‐wide significance (Leslie et al, ; Ludwig et al, ).…”

Section: Introductionmentioning

confidence: 99%

PAX7nucleotide variants and the risk of non‐syndromic orofacial clefts in the Polish population

Gaczkowska

Biedziak

Budner³

et al. 2019

Oral Diseases

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Objective The etiology of non‐syndromic cleft lip with or without cleft palate (nsCL/P) is multifactorial, heterogeneous, and still not completely understood. The aim of the present study was to examine the associations between common and rare PAX7 nucleotide variants and the risk of this common congenital anomaly in a Polish population. Subjects and methods Eight top nsCL/P‐associated PAX7 variants identified in our cleft genome‐wide association study (GWAS) were selected for replication analysis in an independent group of patients and controls (n = 247 and n = 445, respectively). In addition, mutation screening of the PAX7 protein‐coding region was conducted. Results Analysis of the pooled data from the GWAS and replication study confirmed that common PAX7 nucleotide variants are significantly associated with the increased risk of nsCL/P. The strongest individual variant was rs1339062 (c.586 + 15617T > C) with a p‐value = 2.47E−05 (OR = 1.4, 95%CI: 1.20–1.64). Sequencing analysis identified a novel synonymous PAX7 substitution (c.87G > A, p.Val29Val) in a single patient with nsCLP. This transition located in the early exonic position was predicted to disrupt potential splice enhancer elements. Conclusion Our study confirmed that PAX7 is a strong candidate gene for nsCL/P. Nucleotide variants of this gene contribute to the etiology of nsCL/P in the homogenous Polish population.

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“…Orofacial clefts have a complex etiology with both genetic and environmental factors contributing to the condition [1, 2]. Well known candidate genes, which are correlated with the risk of NSCL/P in various populations, include IRF6 , VAX1 and the 8q24 locus [1, 3]. However, their nucleotide variants do not account for all observed NSCL/P cases, emphasizing the need for identifying new genetic factors associated with NSCL/P.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide variants of the cancer predisposing gene CDH1 and the risk of non-syndromic cleft lip with or without cleft palate

et al. 2014

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The CDH1 gene plays an important role during carcinogenesis and craniofacial morphogenesis. Germline mutations in this gene have been described in families presenting syndromic diffuse gastric cancer and orofacial clefts. The aim of this study was to evaluate the association between nucleotide variants of CDH1 and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Six single nucleotide polymorphisms (SNPs) of the CDH1 gene (rs16260, rs9929218, rs7186053, rs4783573, rs16958383, and rs1801552) were genotyped using the TaqMan SNP genotyping assays in 250 patients with NSCL/P and 540 controls from the Polish population. Comparison between patient and control groups showed that the CDH1 rs1801552 variant, under the assumption of recessive model, was associated with a two-fold decrease in the risk of NSCL/P (ORTT vs CT + CC = 0.481, 95 % CI 0.281–0.824, p = 0.007). This association remained statistically significant even after the multiple testing correction. No significant associations with NSCL/P risk were found for the other five tested SNPs. We found a strong association between the cancer predisposing gene CDH1 and the risk of NSCL/P in the Polish population. This result, together with previous observations of co-occurrence of orofacial clefts and a variety of cancer types, suggests the need for replication studies testing rs1801552 in NSCL/P cohorts with a known cancer history.

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Analysis of susceptibility loci for nonsyndromic orofacial clefting in a European trio sample

Cited by 24 publications

References 17 publications

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts

PAX7nucleotide variants and the risk of non‐syndromic orofacial clefts in the Polish population

Nucleotide variants of the cancer predisposing gene CDH1 and the risk of non-syndromic cleft lip with or without cleft palate

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