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Hum Genet. 2017 Mar;136(3):275-286. doi: 10.1007/s00439-016-1754-7. Epub 2017 Jan 4.

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.

Author information

1
Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
2
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
3
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
4
Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, IA, 52242, USA.
5
School of Dental Medicine, University of Puerto Rico, San Juan, 00936, Puerto Rico.
6
CEMIC: Center for Medical Education and Clinical Research, Buenos Aires, 1431, Argentina.
7
ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
8
Laboratory of Congenital Malformation Epidemiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, 21941-617, Brazil.
9
Department of Epidemiology, Institute of Public Health, University of Southern Denmark, 5230, Odense, Denmark.
10
Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO, 80045, USA.
11
Department of Medical Genetics, University of British Columbia, Vancouver, V6H 3N1, Canada.
12
Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, TX, 77030, USA.
13
Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA, 52242, USA.
14
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-617, Brazil.
15
Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, 1101, The Philippines.
16
Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, 52242, USA.
17
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
18
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
19
Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, 15219, USA. marazita@pitt.edu.
20
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA. marazita@pitt.edu.
21
Clinical and Translational Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. marazita@pitt.edu.

Abstract

Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10-8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10-9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

PMID:
28054174
PMCID:
PMC5317097
DOI:
10.1007/s00439-016-1754-7
[Indexed for MEDLINE]
Free PMC Article

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