title: A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.
abstract: Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, 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 Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.|Department of Biostatistics.
authors.forename: Jenna C
authors.initials: JC
authors.lastname: Carlson
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, 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: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.|Department of Biostatistics.|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: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Toby
authors.initials: T
authors.lastname: McHenry
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Resick
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jacobs
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Emanuele
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, 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: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Neiswanger
authors.affiliation: Department of Orthodontics.
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.
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: 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 Medical Genetics, University of British Columbia, Vancouver V6H 3N1, Canada.
authors.forename: L Leigh
authors.initials: LL
authors.lastname: Field
authors.affiliation: Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health; University of the Philippines Manila, Manilla, The Philippines 1000.|Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101.
authors.forename: Carmencita D
authors.initials: CD
authors.lastname: Padilla
authors.affiliation: Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health; University of the Philippines Manila, Manilla, The Philippines 1000.|Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101.
authors.forename: Eva Maria C
authors.initials: EM
authors.lastname: Cutiongco-de la Paz
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 DK-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, NO-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
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authors.affiliation: Department of Epidemiology, College of Public Health.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
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).
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).
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).|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: 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).
authors.forename: Flavia M
authors.initials: FM
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authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Jacqueline T
authors.initials: JT
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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
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authors.affiliation: School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936.
authors.forename: Carmen J
authors.initials: CJ
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authors.affiliation: Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry.
authors.forename: Azeez
authors.initials: A
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authors.affiliation: Department of Orthodontics, University of Dundee, Dundee DD1 4HN, Scotland.
authors.forename: Peter A
authors.initials: PA
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authors.affiliation: Department of Oral and Maxillofacial Surgery. College of Medicine, University of Lagos, Lagos P.M.B. 12003, Nigeria.
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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, 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, 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.
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authors.initials: MA
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authors.affiliation: Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
authors.forename: Fikre
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authors.affiliation: Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
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authors.initials: M
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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: Peking University, School of Stomatology, Beijing 100081, China.
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authors.forename: Javier Enríquez
authors.initials: JE
authors.lastname: de Salamanca
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Seth M
authors.initials: SM
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authors.affiliation: Department of Orthodontics.
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authors.initials: JC
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authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, 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.|Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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authors.initials: ML
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mesh_terms: D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics