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

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

Am J Hum Genet. 2016 Apr 7;98(4):744-54. doi: 10.1016/j.ajhg.2016.02.014. Epub 2016 Mar 24.

Authors

Elizabeth J Leslie¹, Huan Liu², Jenna C Carlson³, John R Shaffer⁴, Eleanor Feingold⁵, George Wehby⁶, Cecelia A Laurie⁷, Deepti Jain⁷, Cathy C Laurie⁷, Kimberly F Doheny⁸, Toby McHenry¹, Judith Resick¹, Carla Sanchez¹, Jennifer Jacobs¹, Beth Emanuele¹, Alexandre R Vieira⁴, Katherine Neiswanger¹, Jennifer Standley⁹, Andrew E Czeizel¹⁰, Frederic Deleyiannis¹¹, Kaare Christensen¹², Ronald G Munger¹³, Rolv T Lie¹⁴, Allen Wilcox¹⁵, Paul A Romitti¹⁶, L Leigh Field¹⁷, Carmencita D Padilla¹⁸, Eva Maria C Cutiongco-de la Paz¹⁹, Andrew C Lidral²⁰, Luz Consuelo Valencia-Ramirez²¹, Ana Maria Lopez-Palacio²², Dora Rivera Valencia²³, Mauricio Arcos-Burgos²⁴, Eduardo E Castilla²⁵, Juan C Mereb²⁶, Fernando A Poletta²⁵, Iêda M Orioli²⁷, Flavia M Carvalho²⁸, Jacqueline T Hecht²⁹, Susan H Blanton³⁰, Carmen J Buxó³¹, Azeez Butali³², Peter A Mossey³³, Wasiu L Adeyemo³⁴, Olutayo James³⁴, Ramat O Braimah³⁵, Babatunde S Aregbesola³⁵, Mekonen A Eshete³⁶, Milliard Deribew³⁶, Mine Koruyucu³⁷, Figen Seymen³⁷, Lian Ma³⁸, Javier Enríquez de Salamanca³⁹, Seth M Weinberg¹, Lina Moreno²⁰, Robert A Cornell⁴⁰, Jeffrey C Murray⁹, Mary L Marazita⁴¹

Affiliations

¹ Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
⁷ Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
⁸ Center for Inherited Disease Research, Johns Hopkins University, Baltimore, MD 21224, USA.
⁹ Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
¹⁰ Foundation for the Community Control of Hereditary Diseases, Budapest 1051, Hungary.
¹¹ Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USA.
¹² Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense 5230, Denmark.
¹³ Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, USA.
¹⁴ Department of Global Public Health and Primary Care, University of Bergen, Bergen 5020, Norway.
¹⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
¹⁶ Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
¹⁷ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
¹⁸ Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manilla 1000, the Philippines.
¹⁹ 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.
²⁰ Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
²¹ Fundación Clínica Noel, Medellin 050012, Colombia.
²² Department of Basic Integrated Studies, College of Dentistry, University of Antioquia, Medellin 050001, Colombia.
²³ Population Genetics and Mutacarcinogenesis Group, University of Antioquia, Medellin 050001, Colombia.
²⁴ 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.
²⁵ 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.
²⁶ ECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, Argentina.
²⁷ 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.
²⁸ 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.
²⁹ Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³⁰ 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.
³¹ School of Dental Medicine, University of Puerto Rico, San Juan 00936, Puerto Rico.
³² Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA.
³³ Department of Orthodontics, University of Dundee, Dundee DD1 4HN, Scotland.
³⁴ Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, P.M.B. 12003, Nigeria.
³⁵ Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University Ile-Ife, Ife-Ife, P.M.B. 13, Nigeria.
³⁶ Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
³⁷ Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
³⁸ School of Stomatology, Peking University, Beijing 100081, China.
³⁹ Hospital Infantil Universitario Niño Jesús, Unidad de Cirugía Plástica, Madrid 28009, Spain.
⁴⁰ Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
⁴¹ 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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Case-Control Studies
Cleft Palate / diagnosis
Cleft Palate / genetics*
DNA-Binding Proteins / genetics*
Disease Models, Animal
Ethnicity / genetics
Genetic Loci
Genome-Wide Association Study
Genotyping Techniques
Humans
Mutation, Missense
Polymorphism, Single Nucleotide*
Risk Factors
Transcription Factors / genetics*
Zebrafish / embryology
Zebrafish / genetics

Substances

DNA-Binding Proteins
GRHL3 protein, human
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding