Journal article
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
Human molecular genetics, Vol.25(13), pp.2862-2872
07/01/2016
DOI: 10.1093/hmg/ddw104
PMCID: PMC5181632
PMID: 27033726
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
), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10
). 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
) 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.
Details
- Title: Subtitle
- 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
- Creators
- Elizabeth J Leslie - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USAJenna C Carlson - Department of BiostatisticsJohn R Shaffer - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USAEleanor Feingold - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USAGeorge Wehby - University of Iowa, Health Management and PolicyCecelia A Laurie - University of WashingtonDeepti Jain - Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USACathy C Laurie - Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USAKimberly F Doheny - Johns Hopkins University School of MedicineToby McHenry - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USAJudith Resick - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USACarla Sanchez - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USAJennifer Jacobs - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USABeth Emanuele - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USAAlexandre R Vieira - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USAKatherine Neiswanger - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USAAndrew C Lidral - Department of OrthodonticsLuz Consuelo Valencia-Ramirez - Universidad de AntioquiaAna Maria Lopez-Palacio - Department of Basic Integrated Studies, College of DentistryMauricio Arcos-Burgos - 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, AustraliaDora Rivera Valencia - Population Genetics and Mutacarcinogenesis Group, University of Antioquia, Medellin 050001, ColombiaAndrew E Czeizel - Foundation for the Community Control of Hereditary Diseases, Budapest 1051, HungaryL Leigh Field - Department of Medical Genetics, University of British Columbia, Vancouver V6H 3N1, CanadaCarmencita D Padilla - Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101Eva Maria C Cutiongco-de la Paz - Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101Frederic Deleyiannis - Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USAKaare Christensen - University of Southern DenmarkRonald G Munger - Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, USARolv T Lie - University of BergenAllen Wilcox - National Institute of Environmental Health SciencesPaul A Romitti - University of Iowa, EpidemiologyEduardo E Castilla - ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics)Juan C Mereb - ECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, ArgentinaFernando A Poletta - ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics)Iêda M Orioli - Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, BrazilFlavia M Carvalho - ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics)Jacqueline T Hecht - Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USASusan H Blanton - Dr. John T. Macdonald Foundation Department of Human Genetics, Hussman Institute for Human Genomics, Mailman School of Medicine, University of Miami, Miami, FL 33124, USACarmen J Buxó - School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936Azeez Butali - University of Iowa, Dental ResearchPeter A Mossey - Department of Orthodontics, University of Dundee, Dundee DD1 4HN, ScotlandWasiu L Adeyemo - Department of Oral and Maxillofacial Surgery. College of Medicine, University of Lagos, Lagos P.M.B. 12003, NigeriaOlutayo James - Department of Oral and Maxillofacial Surgery. College of Medicine, University of Lagos, Lagos P.M.B. 12003, NigeriaRamat O Braimah - Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ife-Ife P.M.B. 13, NigeriaBabatunde S Aregbesola - Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ife-Ife P.M.B. 13, NigeriaMekonen A Eshete - Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, EthiopiaFikre Abate - Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, EthiopiaMine Koruyucu - Department of Pedodontics, Istanbul University, Istanbul 34116, TurkeyFigen Seymen - Department of Pedodontics, Istanbul University, Istanbul 34116, TurkeyLian Ma - Peking University, School of Stomatology, Beijing 100081, ChinaJavier Enríquez de Salamanca - Hospital Infantil Universitario Niño Jesús; Unidad de Cirugía Plástica, Madrid 28009, SpainSeth M Weinberg - University of PittsburghLina Moreno - University of Iowa, Dental ResearchJeffrey C Murray - University of Iowa, Dental ResearchMary L Marazita - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.25(13), pp.2862-2872
- DOI
- 10.1093/hmg/ddw104
- PMID
- 27033726
- PMCID
- PMC5181632
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- England
- Grant note
- S21 MD001830 / NIMHD NIH HHS K99 DE022378 / NIDCR NIH HHS R00 DE022378 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R21 DE016930 / NIDCR NIH HHS R01 DD000295 / NCBDD CDC HHS R01 DE011948 / NIDCR NIH HHS K99 DE025060 / NIDCR NIH HHS U54 MD007587 / NIMHD NIH HHS R01 DE014667 / NIDCR NIH HHS R25 MD007607 / NIMHD NIH HHS R21 DE016877 / NIDCR NIH HHS R01 DE020895 / NIDCR NIH HHS HHSN268201200008I / NHLBI NIH HHS R37 DE008559 / NIDCR NIH HHS K99 DE024571 / NIDCR NIH HHS HHSN268201200008C / NHLBI NIH HHS U01 DE024425 / NIDCR NIH HHS R01 DE009886 / NIDCR NIH HHS R01 DE011931 / NIDCR NIH HHS
- Language
- English
- Date published
- 07/01/2016
- Academic Unit
- Preventive and Community Dentistry; Oral Pathology, Radiology and Medicine; Health Management and Policy; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Economics; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984001888002771
Metrics
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