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Hum Mol Genet. 2016 Jul 1;25(13):2862-2872. Epub 2016 Mar 30.

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.

Author information

1
Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
2
Department of Biostatistics.
3
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
4
Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA 52246, USA.
5
Department of Biostatistics, Genetic Coordinating Center, University of Washington, Seattle, WA 98195, USA.
6
Center for Inherited Disease Research, Johns Hopkins University, Baltimore, MD 21224, USA.
7
Department of Orthodontics.
8
Fundación Clínica Noel, Medellin 050012, Colombia.
9
Department of Basic Integrated Studies, College of Dentistry.
10
Population Genetics and Mutacarcinogenesis Group, University of Antioquia, Medellin 050001, Colombia.
11
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.
12
Foundation for the Community Control of Hereditary Diseases, Budapest 1051, Hungary.
13
Department of Medical Genetics, University of British Columbia, Vancouver V6H 3N1, Canada.
14
Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health; University of the Philippines Manila, Manilla, The Philippines 1000.
15
Philippine Genome Center, University of the Philippines System, Manilla, The Philippines 1101.
16
Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO 80045, USA.
17
Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense DK-5230 Denmark.
18
Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT 84322, USA.
19
Department of Global Public Health and Primary Care, University of Bergen, Bergen, NO-5020 Norway.
20
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
21
Department of Epidemiology, College of Public Health.
22
CEMIC: Center for Medical Education and Clinical Research, Buenos Aires 1431, Argentina.
23
Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-360, Brazil.
24
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics).
25
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at Hospital de Area, El Bolson 8430, Argentina.
26
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil.
27
Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
28
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.
29
School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936.
30
Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry.
31
Department of Orthodontics, University of Dundee, Dundee DD1 4HN, Scotland.
32
Department of Oral and Maxillofacial Surgery. College of Medicine, University of Lagos, Lagos P.M.B. 12003, Nigeria.
33
Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ife-Ife P.M.B. 13, Nigeria.
34
Surgical Department, School of Medicine, Addis Ababa University, Addis Ababa, P.O. Box 26493, Ethiopia.
35
Department of Pedodontics, Istanbul University, Istanbul 34116, Turkey.
36
Peking University, School of Stomatology, Beijing 100081, China.
37
Hospital Infantil Universitario Niño Jesús; Unidad de Cirugía Plástica, Madrid 28009, Spain.
38
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
39
Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA marazita@pitt.edu.
40
Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

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 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). 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 × 10-8) 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.

PMID:
27033726
PMCID:
PMC5181632
DOI:
10.1093/hmg/ddw104
[Indexed for MEDLINE]
Free PMC Article

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