Journal article
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
Human genetics, Vol.136(3), pp.275-286
03/2017
DOI: 10.1007/s00439-016-1754-7
PMCID: PMC5317097
PMID: 28054174
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.
Details
- Title: Subtitle
- 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
- Creators
- Elizabeth Leslie - Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh Pittsburgh PA 15219 USAJenna Carlson - Department of Biostatistics, Graduate School of Public Health University of Pittsburgh Pittsburgh PA 15261 USAJohn Shaffer - Department of Human Genetics, Graduate School of Public Health University of Pittsburgh Pittsburgh PA 15261 USAAzeez Butali - Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry University of Iowa Iowa City IA 52242 USACarmen Buxó - School of Dental Medicine University of Puerto Rico San Juan 00936 Puerto RicoEduardo Castilla - Laboratory of Congenital Malformation Epidemiology Oswaldo Cruz Institute, FIOCRUZ Rio de Janeiro 21941-617 BrazilKaare Christensen - Department of Epidemiology, Institute of Public Health University of Southern Denmark 5230 Odense DenmarkFred Deleyiannis - Department of Surgery, Plastic and Reconstructive Surgery University of Colorado School of Medicine Denver CO 80045 USAL Leigh Field - Department of Medical Genetics University of British Columbia Vancouver V6H 3N1 CanadaJacqueline Hecht - Department of Pediatrics McGovern Medical School and School of Dentistry UT Health at Houston Houston TX 77030 USALina Moreno - Department of Orthodontics, College of Dentistry University of Iowa Iowa City IA 52242 USAIeda Orioli - Department of Genetics, Institute of Biology Federal University of Rio de Janeiro Rio de Janeiro 21941-617 BrazilCarmencita Padilla - Department of Pediatrics, College of Medicine; and Institute of Human Genetics, National Institutes of Health University of the Philippines Manila Manila 1101 The PhilippinesAlexandre Vieira - Department of Human Genetics, Graduate School of Public Health University of Pittsburgh Pittsburgh PA 15261 USAGeorge Wehby - Department of Health Management and Policy, College of Public Health University of Iowa Iowa City IA 52242 USAEleanor Feingold - Department of Human Genetics, Graduate School of Public Health University of Pittsburgh Pittsburgh PA 15261 USASeth Weinberg - Department of Oral Biology, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh Pittsburgh PA 15219 USAJeffrey Murray - Department of Pediatrics, Carver College of Medicine University of Iowa Iowa City IA 52242 USATerri Beaty - Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD 21205 USAMary Marazita - Clinical and Translational Science, School of Medicine University of Pittsburgh Pittsburgh PA 15261 USA
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.136(3), pp.275-286
- DOI
- 10.1007/s00439-016-1754-7
- PMID
- 28054174
- PMCID
- PMC5317097
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Publisher
- Springer Berlin Heidelberg; Berlin/Heidelberg
- Grant note
- DE025060; HG007485; DE016148 / National Institutes of Health (http://dx.doi.org/10.13039/100000002)
- Language
- English
- Date published
- 03/2017
- Academic Unit
- Preventive and Community Dentistry; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9984025370002771
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