Journal article
Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate
PLoS genetics, Vol.11(3), pp.e1005059-e1005059
03/2015
DOI: 10.1371/journal.pgen.1005059
PMCID: PMC4370697
PMID: 25798845
Abstract
Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10(-13); adjusted p= 2.2 x 10(-3)). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans.
Details
- Title: Subtitle
- Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate
- Creators
- Zena T Wolf - Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of AmericaHarrison A Brand - Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of AmericaJohn R Shaffer - Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of AmericaElizabeth J Leslie - Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of AmericaBoaz Arzi - Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of AmericaCali E Willet - Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, AustraliaTimothy C Cox - Department of Pediatrics (Division of Craniofacial Medicine), University of Washington, Seattle, Washington, United States of America; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, United States of America; Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, AustraliaToby McHenry - Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of AmericaNicole Narayan - Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of AmericaEleanor Feingold - Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of AmericaXioajing Wang - Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of AmericaSaundra Sliskovic - Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of AmericaNili Karmi - Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of AmericaNoa Safra - Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of AmericaCarla Sanchez - Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of AmericaFrederic W B Deleyiannis - Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Aurora, Colorado, United States of AmericaJeffrey C Murray - Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of AmericaClaire M Wade - Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, AustraliaMary L Marazita - Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America; Clinical and Translational Science and Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of AmericaDanika L Bannasch - Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.11(3), pp.e1005059-e1005059
- DOI
- 10.1371/journal.pgen.1005059
- PMID
- 25798845
- PMCID
- PMC4370697
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science; United States
- Grant note
- T15 LM007059 / NLM NIH HHS R01-DE022532 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS U01 DE020057 / NIDCR NIH HHS T15-LM007059 / NLM NIH HHS R01-DE016148 / NIDCR NIH HHS R01 DE022532 / NIDCR NIH HHS
- Language
- English
- Date published
- 03/2015
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984025461502771
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