title: Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.
abstract: Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10-8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10-9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.
authors.affiliation: Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Elizabeth J
authors.identifier: 0000-0002-5735-1712
authors.initials: EJ
authors.lastname: Leslie
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Jenna C
authors.initials: JC
authors.lastname: Carlson
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Shaffer
authors.affiliation: Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: Azeez
authors.initials: A
authors.lastname: Butali
authors.affiliation: School of Dental Medicine, University of Puerto Rico, San Juan, 00936, Puerto Rico.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Buxó
authors.affiliation: CEMIC: Center for Medical Education and Clinical Research, Buenos Aires, 1431, Argentina.|ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.|Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, 21941-617, Brazil.
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Castilla
authors.affiliation: Department of Epidemiology, Institute of Public Health, University of Southern Denmark, 5230, Odense, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO, 80045, USA.
authors.forename: Fred W B
authors.initials: FW
authors.lastname: Deleyiannis
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Leigh Field
authors.affiliation: Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, TX, 77030, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.affiliation: Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Moreno
authors.affiliation: ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.|Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-617, Brazil.
authors.forename: Ieda M
authors.initials: IM
authors.lastname: Orioli
authors.affiliation: Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, 1101, The Philippines.
authors.forename: Carmencita
authors.initials: C
authors.lastname: Padilla
authors.affiliation: Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Vieira
authors.affiliation: Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Wehby
authors.affiliation: Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA.|Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.affiliation: Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Weinberg
authors.affiliation: Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA. marazita@pitt.edu.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA. marazita@pitt.edu.|Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. marazita@pitt.edu.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
mesh_terms: D002874:Chromosome Mapping; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins