A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

Elizabeth J Leslie; Huan Liu; 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; Jennifer Standley; Andrew E Czeizel; Frederic Deleyiannis; Kaare Christensen; Ronald G Munger; Rolv T Lie; Allen Wilcox; Paul A Romitti; L Leigh Field; Carmencita D Padilla; Eva Maria C Cutiongco-de la Paz; Andrew C Lidral; Luz Consuelo Valencia-Ramirez; Ana Maria Lopez-Palacio; Dora Rivera Valencia; Mauricio Arcos-Burgos; 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; Milliard Deribew; Mine Koruyucu; Figen Seymen; Lian Ma; Javier Enríquez de Salamanca; Seth M Weinberg; Lina Moreno; Robert A Cornell; Jeffrey C Murray; Mary L Marazita

doi:10.1016/j.ajhg.2016.02.014

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A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

Journal article

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Peer reviewed

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

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

American journal of human genetics, Vol.98(4), pp.744-754

04/07/2016

DOI: 10.1016/j.ajhg.2016.02.014

PMCID: PMC4833215

PMID: 27018472

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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.

Cleft Palate - diagnosis

Genome-Wide Association Study

Humans

Risk Factors

Cleft Palate - genetics

Genetic Loci

Mutation, Missense

Transcription Factors - genetics

DNA-Binding Proteins - genetics

Genotyping Techniques

Zebrafish - embryology

Case-Control Studies

Zebrafish - genetics

Animals

Ethnic Groups - genetics

Polymorphism, Single Nucleotide

Disease Models, Animal

Details

Title: Subtitle: A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3
Creators: Elizabeth J Leslie - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Huan Liu - 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
Jenna C Carlson - 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
John R Shaffer - 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
Eleanor Feingold - 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
George Wehby - Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52246, USA
Cecelia A Laurie - University of Washington
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 - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Judith Resick - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Carla Sanchez - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Jennifer Jacobs - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Beth Emanuele - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Alexandre R Vieira - 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
Katherine Neiswanger - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Jennifer Standley - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Andrew E Czeizel - Foundation for the Community Control of Hereditary Diseases, Budapest 1051, Hungary
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 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 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, University of Iowa, Iowa City, IA 52246, USA
L Leigh Field - Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Carmencita D Padilla - Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manilla 1000, the Philippines
Eva Maria C Cutiongco-de la Paz - 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
Andrew C Lidral - Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA
Luz Consuelo Valencia-Ramirez - Fundación Clínica Noel, Medellin 050012, Colombia
Ana Maria Lopez-Palacio - Department of Basic Integrated Studies, College of Dentistry, University of Antioquia, Medellin 050001, Colombia
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
Eduardo E Castilla - 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
Juan C Mereb - ECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, Argentina
Fernando A Poletta - 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
Iêda M Orioli - 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
Flavia M Carvalho - 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
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 00936, Puerto Rico
Azeez Butali - Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA
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 Ile-Ife, Ife-Ife, P.M.B. 13, Nigeria
Babatunde S Aregbesola - Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University Ile-Ife, 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
Milliard Deribew - 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 - School of Stomatology, Peking University, Beijing 100081, China
Javier Enríquez de Salamanca - Hospital Infantil Universitario Niño Jesús, Unidad de Cirugía Plástica, Madrid 28009, Spain
Seth M Weinberg - Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
Lina Moreno - Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA
Robert A Cornell - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Jeffrey C Murray - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Mary L Marazita - 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
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.98(4), pp.744-754
DOI: 10.1016/j.ajhg.2016.02.014
PMID: 27018472
PMCID: PMC4833215
NLM abbreviation: Am J Hum Genet
ISSN: 1537-6605
eISSN: 1537-6605
Publisher: United States
Grant note: S21 MD001830 / NIMHD NIH HHS R00 DE022378 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R21 DE016930 / NIDCR NIH HHS M01 RR000084 / NCRR NIH HHS R01 DE011948 / NIDCR NIH HHS U01-DE018993 / NIDCR NIH HHS U01 DE018993 / NIDCR NIH HHS K99 DE025060 / NIDCR NIH HHS U54 MD007587 / NIMHD NIH HHS R01 DE023575 / NIDCR NIH HHS R25 MD007607 / NIMHD NIH HHS R01 DE020895 / NIDCR NIH HHS HHSN268201200008I / NHLBI NIH HHS X01-HG007845 / NHGRI NIH HHS R37 DE008559 / NIDCR NIH HHS HHSN268201200008I / PHS HHS K99 DE024571 / NIDCR NIH HHS R01-DE020895 / NIDCR NIH HHS R01-DE016148 / 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: 04/07/2016
Academic Unit: Preventive and Community Dentistry; Oral Pathology, Radiology and Medicine; Health Management and Policy; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Nursing; Orthodontics; Anatomy and Cell Biology; International Programs; Stead Family Department of Pediatrics; Epidemiology; Economics; Public Policy Center (Archive); Dental Research
Record Identifier: 9983995040702771

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