Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes |
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| Authors: | Jenna C. Carlson Jennifer Standley Aline Petrin John R. Shaffer Azeez Butali Carmen J. Buxó Eduardo Castilla Kaare Christensen Frederic W.‐D. Deleyiannis Jacqueline T. Hecht L. Leigh Field Ariuntuul Garidkhuu Lina M. Moreno Uribe Natsume Nagato Ieda M. Orioli Carmencita Padilla Fernando Poletta Satoshi Suzuki Alexandre R. Vieira George L. Wehby Seth M. Weinberg Terri H. Beaty Eleanor Feingold Jeffrey C. Murray Mary L. Marazita Elizabeth J. Leslie |
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| Affiliation: | 1. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;2. Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America;3. Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, Iowa, United States of America;4. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;5. Department of Oral Pathology, Radiology and Medicine, Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, Iowa, United States of America;6. Dental and Craniofacial Genomics Center, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico;7. CEMIC: Center for Medical Education and Clinical Research, Buenos Aires, Argentina;8. Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark;9. Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, Colorado, United States of America;10. Department of Pediatrics, McGovern Medical School and School of Dentistry UT Health at Houston, Houston, Texas, United States of America;11. Department of Medical Genetics, University of British Columbia, Vancouver, Canada;12. Division of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Japan;13. School of Dentistry, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia;14. Division of Research and Treatment for Oral and Maxillofacial Congenital Anomalies, School of Dentistry, Aichi‐Gakuin University, Nisshin, Japan;15. ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil;16. Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;17. Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila, Philippines;18. Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, Philippines;19. Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;20. Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, Iowa, United States of America;21. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America;22. Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America |
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| Abstract: | Orofacial 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. |
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| Keywords: | complex trait gene– gene interaction genetic modifier orofacial cleft |
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