A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.,American Journal of Human Genetics

当前位置： X-MOL 学术 › Am. J. Hum. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2016-03-24 , DOI: 10.1016/j.ajhg.2016.02.014
Elizabeth J Leslie ₁ , Huan Liu ₂ , Jenna C Carlson ₃ , John R Shaffer ₄ , Eleanor Feingold ₅ , George Wehby ₆ , Cecelia A Laurie ₇ , Deepti Jain ₇ , Cathy C Laurie ₇ , Kimberly F Doheny ₈ , Toby McHenry ₁ , Judith Resick ₁ , Carla Sanchez ₁ , Jennifer Jacobs ₁ , Beth Emanuele ₁ , Alexandre R Vieira ₄ , Katherine Neiswanger ₁ , Jennifer Standley ₉ , Andrew E Czeizel ₁₀ , Frederic Deleyiannis ₁₁ , Kaare Christensen ₁₂ , Ronald G Munger ₁₃ , Rolv T Lie ₁₄ , Allen Wilcox ₁₅ , Paul A Romitti ₁₆ , L Leigh Field ₁₇ , Carmencita D Padilla ₁₈ , Eva Maria C Cutiongco-de la Paz ₁₉ , Andrew C Lidral ₂₀ , Luz Consuelo Valencia-Ramirez ₂₁ , Ana Maria Lopez-Palacio ₂₂ , Dora Rivera Valencia ₂₃ , Mauricio Arcos-Burgos ₂₄ , Eduardo E Castilla ₂₅ , Juan C Mereb ₂₆ , Fernando A Poletta ₂₅ , Iêda M Orioli ₂₇ , Flavia M Carvalho ₂₈ , Jacqueline T Hecht ₂₉ , Susan H Blanton ₃₀ , Carmen J Buxó ₃₁ , Azeez Butali ₃₂ , Peter A Mossey ₃₃ , Wasiu L Adeyemo ₃₄ , Olutayo James ₃₄ , Ramat O Braimah ₃₅ , Babatunde S Aregbesola ₃₅ , Mekonen A Eshete ₃₆ , Milliard Deribew ₃₆ , Mine Koruyucu ₃₇ , Figen Seymen ₃₇ , Lian Ma ₃₈ , Javier Enríquez de Salamanca ₃₉ , Seth M Weinberg ₁ , Lina Moreno ₂₀ , Robert A Cornell ₄₀ , Jeffrey C Murray ₉ , Mary L Marazita ₄₁

Affiliation

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

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.

中文翻译：

非综合征性腭裂的全基因组关联研究确定了 GRHL3 的病因错义变异。

腭裂 (CP) 是一种常见的出生缺陷，每 2,500 名活产婴儿中就有 1 名发生。大约一半患有 CP 的婴儿有症状，表现出其他身体和认知障碍。另一半患有非综合征 CP，迄今为止，很少有与非综合征 CP 风险相关的基因被表征。为了确定这些风险因素，我们对这种疾病进行了全基因组关联研究。我们发现了与 GRHL3 中的错义变体（p.Thr454Met [c.1361C>T]；rs41268753；p = 4.08 × 10(-9)）的全基因组显着关联，并将结果复制到独立的病例和对照样本中科目。在发现和复制样本中，rs41268753 增加了 CP 的风险（OR = 8.3，95% CI 4.1-16.8；OR = 2.16，95% CI 1.43-3.27）。在荧光素酶反式激活测定中，p。Thr454Met 的活性约为野生型 GRHL3 的三分之一，在斑马鱼胚胎中，它会扰乱周皮发育。我们得出结论，该突变是非综合征性 CP 的病因变异，并且是迄今为止确定的非综合征性口颌裂的少数功能变异之一。这一发现加深了我们对颅面发育遗传基础的理解，并可能最终导致复发风险预测、治疗和预后的改善。

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11