Journal article
Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes
Genetic epidemiology, Vol.41(8), pp.887-897
12/2017
DOI: 10.1002/gepi.22090
PMCID: PMC5728176
PMID: 29124805
Abstract
ABSTRACT\nOrofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome‐wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.
Details
- Title: Subtitle
- Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes
- Creators
- Jenna C Carlson - University of PittsburghJennifer Standley - University of IowaAline Petrin - University of IowaJohn R Shaffer - University of PittsburghAzeez Butali - University of IowaCarmen J Buxó - University of Puerto RicoEduardo Castilla - CEMIC: Center for Medical Education and Clinical ResearchKaare Christensen - University of Southern DenmarkFrederic W.‐D Deleyiannis - University of Colorado School of MedicineJacqueline T Hecht - McGovern Medical School and School of Dentistry UT Health at HoustonL. Leigh Field - University of British ColumbiaAriuntuul Garidkhuu - Mongolian National University of Medical SciencesLina M Moreno Uribe - University of IowaNatsume Nagato - Aichi‐Gakuin UniversityIeda M Orioli - Federal University of Rio de JaneiroCarmencita Padilla - University of the Philippines ManilaFernando Poletta - CEMIC: Center for Medical Education and Clinical ResearchSatoshi Suzuki - Aichi‐Gakuin UniversityAlexandre R Vieira - University of PittsburghGeorge L Wehby - University of IowaSeth M Weinberg - University of PittsburghTerri H Beaty - Johns Hopkins Bloomberg School of Public HealthEleanor Feingold - University of PittsburghJeffrey C Murray - University of IowaMary L Marazita - University of PittsburghElizabeth J Leslie - Emory University
- Resource Type
- Journal article
- Publication Details
- Genetic epidemiology, Vol.41(8), pp.887-897
- DOI
- 10.1002/gepi.22090
- PMID
- 29124805
- PMCID
- PMC5728176
- NLM abbreviation
- Genet Epidemiol
- ISSN
- 0741-0395
- eISSN
- 1098-2272
- Number of pages
- 11
- Grant note
- JSPS KAKENHI (JP17K11863; 24249092)\nRobert Wood Johnson Foundation (72429)\nNational Institute of Dental and Craniofacial Research (DE008559; DE009886; DE011931; DE011948; DE012472; DE014581; DE014667; DE016148; DE016930; DE018993; DE024425; DE025060)\nJohns Hopkins Center for Inherited Disease Research (HHSN268201200008I)\nNational Institutes of Health (DE025060 (; X01‐HG007485; DE016148; DE024425; DE008559; DE009886; DE016930; DE014667; DE012472; DE011931; DE011948; U01‐DD000295; DE022378; K99‐DE024571; S21‐MD001830; DE014581; DE018993)
- Language
- English
- Date published
- 12/2017
- 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
- 9984065814202771
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