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

Elizabeth J Leslie; Jenna C Carlson; John R Shaffer; Eleanor Feingold; George Wehby; Cecelia A Laurie; Deepti Jain; Cathy C Laurie; Kimberly F Doheny; Toby McHenry; Judith Resick; Carla Sanchez; Jennifer Jacobs; Beth Emanuele; Alexandre R Vieira; Katherine Neiswanger; Andrew C Lidral; Luz Consuelo Valencia-Ramirez; Ana Maria Lopez-Palacio; Dora Rivera Valencia; Mauricio Arcos-Burgos; Andrew E Czeizel; L Leigh Field; Carmencita D Padilla; Eva Maria C Cutiongco-de la Paz; Frederic Deleyiannis; Kaare Christensen; Ronald G Munger; Rolv T Lie; Allen Wilcox; Paul A Romitti; Eduardo E Castilla; Juan C Mereb; Fernando A Poletta; Iêda M Orioli; Flavia M Carvalho; Jacqueline T Hecht; Susan H Blanton; Carmen J Buxó; Azeez Butali; Peter A Mossey; Wasiu L Adeyemo; Olutayo James; Ramat O Braimah; Babatunde S Aregbesola; Mekonen A Eshete; Fikre Abate; Mine Koruyucu; Figen Seymen; Lian Ma; Javier Enríquez de Salamanca; Seth M Weinberg; Lina Moreno; Jeffrey C Murray; Mary L Marazita

doi:10.1093/hmg/ddw104

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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

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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

Elizabeth J Leslie, Jenna C Carlson, John R Shaffer, Eleanor Feingold, George Wehby, Cecelia A Laurie, Deepti Jain, Cathy C Laurie, Kimberly F Doheny, Toby McHenry, …

Human molecular genetics, Vol.25(13), pp.2862-2872

2016-07-01

DOI: https://doi.org/10.1093/hmg/ddw104

PMCID: PMC5181632

PMID: 27033726

Abstract

European Continental Ancestry Group - genetics

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Risk Factors

Asian Continental Ancestry Group - genetics

Male

Cleft Palate - genetics

Genetic Loci

Chromosomes, Human, Pair 17 - genetics

Chromosomes, Human, Pair 19 - genetics

Chromosomes, Human, Pair 2 - genetics

Cleft Lip - genetics

Ethnic Groups

Polymorphism, Single Nucleotide - genetics

Female

African Continental Ancestry Group - genetics

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.49 Dentistry & Oral Medicine; 1.49.1017 Cleft Palate
Web Of Science research areas: Biochemistry & Molecular Biology; Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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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
Creators: Elizabeth J Leslie - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Jenna C Carlson - Department of Biostatistics
John R Shaffer - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Eleanor Feingold - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
George Wehby - Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52246, USA
Cecelia A Laurie - Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA
Deepti Jain - Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA
Cathy C Laurie - Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA
Kimberly F Doheny - Center for Inherited Disease Research, Johns Hopkins University, Baltimore, MD 21224, USA
Toby McHenry - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Judith Resick - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Carla Sanchez - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Jennifer Jacobs - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Beth Emanuele - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Alexandre R Vieira - Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Katherine Neiswanger - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Andrew C Lidral - Department of Orthodontics
Luz Consuelo Valencia-Ramirez - Fundación Clínica Noel, Medellin 050012, Colombia
Ana Maria Lopez-Palacio - Department of Basic Integrated Studies, College of Dentistry
Dora Rivera Valencia - Population Genetics and Mutacarcinogenesis Group, University of Antioquia, Medellin 050001, Colombia
Mauricio 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, Australia
Andrew E Czeizel - Foundation for the Community Control of Hereditary Diseases, Budapest 1051, Hungary
L Leigh Field - Department of Medical Genetics, University of British Columbia, Vancouver V6H 3N1, Canada
Carmencita D Padilla - Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101
Eva Maria C Cutiongco-de la Paz - Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101
Frederic Deleyiannis - Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USA
Kaare Christensen - Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense DK-5230 Denmark
Ronald G Munger - Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, USA
Rolv T Lie - Department of Global Public Health and Primary Care, University of Bergen, Bergen, NO-5020 Norway
Allen Wilcox - Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
Paul A Romitti - Department of Epidemiology, College of Public Health
Eduardo 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, Argentina
Fernando 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, Brazil
Flavia 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, USA
Susan 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, USA
Carmen J Buxó - School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936
Azeez Butali - Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry
Peter A Mossey - Department of Orthodontics, University of Dundee, Dundee DD1 4HN, Scotland
Wasiu L Adeyemo - Department of Oral and Maxillofacial Surgery. College of Medicine, University of Lagos, Lagos P.M.B. 12003, Nigeria
Olutayo James - Department of Oral and Maxillofacial Surgery. College of Medicine, University of Lagos, Lagos P.M.B. 12003, Nigeria
Ramat O Braimah - Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ife-Ife P.M.B. 13, Nigeria
Babatunde S Aregbesola - Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ife-Ife P.M.B. 13, Nigeria
Mekonen A Eshete - Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia
Fikre Abate - Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia
Mine Koruyucu - Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey
Figen Seymen - Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey
Lian Ma - Peking University, School of Stomatology, Beijing 100081, China
Javier Enríquez de Salamanca - Hospital Infantil Universitario Niño Jesús; Unidad de Cirugía Plástica, Madrid 28009, Spain
Seth M Weinberg - Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Lina Moreno - Department of Orthodontics
Jeffrey C Murray - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Mary L Marazita - Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Publication Details: Human molecular genetics, Vol.25(13), pp.2862-2872
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
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 27033726
PMCID: PMC5181632
Record Identifier: 991031576845302976