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

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.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Wolf, ZT Brand, HA Shaffer, JR john.r.shaffer@pitt.edu JRS51 Leslie, EJ ejl40@pitt.edu EJL40 Arzi, B Willet, CE Cox, TC McHenry, T tog1@pitt.edu TOG1 Narayan, N Feingold, E feingold@pitt.edu FEINGOLD Wang, X Sliskovic, S Karmi, N Safra, N Sanchez, C cab28@pitt.edu CAB28 Deleyiannis, FWB Murray, JC Wade, CM Marazita, ML marazita@pitt.edu MARAZITA Bannasch, DL
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Leeb, Tosso UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	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:	30 Mar 2021 13:56
URI:	http://d-scholarship.pitt.edu/id/eprint/28528

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