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Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate

Wolf, ZT and Brand, HA and Shaffer, JR and Leslie, EJ and Arzi, B and Willet, CE and Cox, TC and McHenry, T and Narayan, N and Feingold, E and Wang, X and Sliskovic, S and Karmi, N and Safra, N and Sanchez, C and Deleyiannis, FWB and Murray, JC and Wade, CM and Marazita, ML and Bannasch, DL (2015) Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate. PLoS Genetics, 11 (3). ISSN 1553-7390

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Abstract

© 2015 Wolf et al. 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<sup>-13</sup>; adjusted p= 2.2 x 10<sup>-3</sup>). 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<sup>-6</sup>) 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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wolf, ZT
Brand, HA
Shaffer, JRjohn.r.shaffer@pitt.eduJRS51
Leslie, EJejl40@pitt.eduEJL40
Arzi, B
Willet, CE
Cox, TC
McHenry, Ttog1@pitt.eduTOG1
Narayan, N
Feingold, Efeingold@pitt.eduFEINGOLD
Wang, X
Sliskovic, S
Karmi, N
Safra, N
Sanchez, Ccab28@pitt.eduCAB28
Deleyiannis, FWB
Murray, JC
Wade, CM
Marazita, MLmarazita@pitt.eduMARAZITA
Bannasch, DL
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLeeb, TossoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 23 March 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Genetics
Volume: 11
Number: 3
DOI or Unique Handle: 10.1371/journal.pgen.1005059
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
School of Dental Medicine > Dental Science
School of Medicine > Clinical and Translational Science
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 05 Jul 2016 17:27
Last Modified: 02 Feb 2019 16:57
URI: http://d-scholarship.pitt.edu/id/eprint/28528

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