1. Strong Association of Variants around FOXE1 and Orofacial Clefting
- Author
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Margrieta A. Alblas, Sandra Barth, Thomas Kreusch, Régine P.M. Steegers-Theunissen, Markus Martini, Bert Braumann, Anne M. Molloy, Stefanie Nowak, Borut Peterlin, B. Lippke, Peter A. Mossey, Andreas Jäger, Markus M. Nöthen, Peter Hoffmann, E. Mangold, Heiko Reutter, Mario Paredes-Zenteno, Alexander Hemprich, Kerstin U. Ludwig, Bernd Pötzsch, Anne C. Böhmer, Stefan Herms, Sergio G. Munoz-Jimenez, Augusto Rojas-Martinez, Rocio Ortiz-Lopez, Michele Rubini, Michael Knapp, Medical Oncology, and Obstetrics & Gynecology
- Subjects
Male ,Genotype ,Cleft Lip ,Genes, Recessive ,Single-nucleotide polymorphism ,Biology ,association study ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,White People ,Risk Factors ,Cleft lip and palate ,Independent samples ,Genetic model ,Ethnicity ,medicine ,Humans ,Polymorphism ,General Dentistry ,Genotyping ,Genetics ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Models, Genetic ,Homozygote ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Medical genetics ,FOXE1 gene ,Chromosome Mapping ,Genetic Variation ,Forkhead Transcription Factors ,medicine.disease ,Indians, Central American ,Cleft Palate ,Phenotype ,Case-Control Studies ,Female ,FOXE1 ,Congenital disorder - Abstract
Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: pEurope = 6.50 × 10−06, pMayan = .0151; rs3758249: pEurope = 2.41 × 10−05, pMayan = .0299), no association was found in nsCPO ( p > .05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P ( p = .016) and nsCPO ( p = .043). A meta-analysis of all data revealed a genomewide significant result for nsCL/P ( p = 1.31 × 10−08), which became more significant when nsCPO cases were added ( pnsOFC = 1.56 × 10−09). These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO.
- Published
- 2014