title: A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.
abstract: 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.
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Leslie
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA; State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; 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: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, 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: John R
authors.initials: JR
authors.lastname: Shaffer
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, 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 Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wehby
authors.affiliation: Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
authors.forename: Cecelia A
authors.initials: CA
authors.lastname: Laurie
authors.affiliation: Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Laurie
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Toby
authors.initials: T
authors.lastname: McHenry
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Resick
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jacobs
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Emanuele
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, 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: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Neiswanger
authors.affiliation: Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Standley
authors.affiliation: Foundation for the Community Control of Hereditary Diseases, Budapest 1051, Hungary.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Czeizel
authors.affiliation: Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Deleyiannis
authors.affiliation: Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense 5230, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Munger
authors.affiliation: Department of Global Public Health and Primary Care, University of Bergen, Bergen 5020, Norway.
authors.forename: Rolv T
authors.initials: RT
authors.lastname: Lie
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Wilcox
authors.affiliation: Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: L Leigh
authors.initials: LL
authors.lastname: Field
authors.affiliation: Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manilla 1000, the Philippines.
authors.forename: Carmencita D
authors.initials: CD
authors.lastname: Padilla
authors.affiliation: Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manilla 1000, the Philippines; Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manilla 1000, the Philippines; Philippine Genome Center, University of the Philippines, Manilla 1101, the Philippines.
authors.forename: Eva Maria C
authors.initials: EM
authors.lastname: Cutiongco-de la Paz
authors.affiliation: Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lidral
authors.affiliation: Fundación Clínica Noel, Medellin 050012, Colombia.
authors.forename: Luz Consuelo
authors.initials: LC
authors.lastname: Valencia-Ramirez
authors.affiliation: Department of Basic Integrated Studies, College of Dentistry, University of Antioquia, Medellin 050001, Colombia.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Lopez-Palacio
authors.affiliation: Population Genetics and Mutacarcinogenesis Group, University of Antioquia, Medellin 050001, Colombia.
authors.forename: Dora Rivera
authors.initials: DR
authors.lastname: Valencia
authors.affiliation: Genomics and Predictive Medicine, Genome Biology Department, John Curtin School of Medical Research, ANU College of Medicine, Biology & Environment, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.affiliation: CEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina; Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro 21941-617, Brazil.
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Castilla
authors.affiliation: ECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, Argentina.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Mereb
authors.affiliation: CEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina; Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil; ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro 21941-617, Brazil.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Poletta
authors.affiliation: ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro 21941-617, Brazil; Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil.
authors.forename: Iêda M
authors.initials: IM
authors.lastname: Orioli
authors.affiliation: CEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina; Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil.
authors.forename: Flavia M
authors.initials: FM
authors.lastname: Carvalho
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, Mailman School of Medicine, University of Miami, Miami, FL 33124, USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
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: 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: Department of Orthodontics, University of Dundee, Dundee DD1 4HN, Scotland.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Mossey
authors.affiliation: Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, P.M.B. 12003, Nigeria.
authors.forename: Wasiu L
authors.initials: WL
authors.lastname: Adeyemo
authors.affiliation: Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, P.M.B. 12003, Nigeria.
authors.forename: Olutayo
authors.initials: O
authors.lastname: James
authors.affiliation: Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University Ile-Ife, Ife-Ife, P.M.B. 13, Nigeria.
authors.forename: Ramat O
authors.initials: RO
authors.lastname: Braimah
authors.affiliation: Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University Ile-Ife, Ife-Ife, P.M.B. 13, Nigeria.
authors.forename: Babatunde S
authors.initials: BS
authors.lastname: Aregbesola
authors.affiliation: Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
authors.forename: Mekonen A
authors.initials: MA
authors.lastname: Eshete
authors.affiliation: Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
authors.forename: Milliard
authors.initials: M
authors.lastname: Deribew
authors.affiliation: Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
authors.forename: Mine
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authors.affiliation: Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
authors.forename: Figen
authors.initials: F
authors.lastname: Seymen
authors.affiliation: School of Stomatology, Peking University, Beijing 100081, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Ma
authors.affiliation: Hospital Infantil Universitario Niño Jesús, Unidad de Cirugía Plástica, Madrid 28009, Spain.
authors.forename: Javier Enríquez
authors.initials: JE
authors.lastname: de Salamanca
authors.affiliation: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Weinberg
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: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cornell
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: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: marazita@pitt.edu.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005006:Ethnicity / Q000235:genetics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; D014157:Transcription Factors