title: Strong association of variants around FOXE1 and orofacial clefting.
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: p Europe = 6.50 × 10(-06), p Mayan = .0151; rs3758249: p Europe = 2.41 × 10(-05), p Mayan = .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 (p nsOFC = 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.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: K U
authors.initials: KU
authors.lastname: Ludwig
authors.forename: A C
authors.initials: AC
authors.lastname: Böhmer
authors.forename: M
authors.initials: M
authors.lastname: Rubini
authors.forename: P A
authors.initials: PA
authors.lastname: Mossey
authors.forename: S
authors.initials: S
authors.lastname: Herms
authors.forename: S
authors.initials: S
authors.lastname: Nowak
authors.forename: H
authors.initials: H
authors.lastname: Reutter
authors.forename: M A
authors.initials: MA
authors.lastname: Alblas
authors.forename: B
authors.initials: B
authors.lastname: Lippke
authors.forename: S
authors.initials: S
authors.lastname: Barth
authors.forename: M
authors.initials: M
authors.lastname: Paredes-Zenteno
authors.forename: S G
authors.initials: SG
authors.lastname: Muñoz-Jimenez
authors.forename: R
authors.initials: R
authors.lastname: Ortiz-Lopez
authors.forename: T
authors.initials: T
authors.lastname: Kreusch
authors.forename: A
authors.initials: A
authors.lastname: Hemprich
authors.forename: M
authors.initials: M
authors.lastname: Martini
authors.forename: B
authors.initials: B
authors.lastname: Braumann
authors.forename: A
authors.initials: A
authors.lastname: Jäger
authors.forename: B
authors.initials: B
authors.lastname: Pötzsch
authors.forename: A
authors.initials: A
authors.lastname: Molloy
authors.forename: B
authors.initials: B
authors.lastname: Peterlin
authors.forename: P
authors.initials: P
authors.lastname: Hoffmann
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: A
authors.initials: A
authors.lastname: Rojas-Martinez
authors.forename: M
authors.initials: M
authors.lastname: Knapp
authors.forename: R P
authors.initials: RP
authors.lastname: Steegers-Theunissen
authors.forename: E
authors.initials: E
authors.lastname: Mangold
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007197:Indians, Central American / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors
keywords: association study; case-control; cleft lip; cleft palate; genetic model; single-nucleotide polymorphism