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Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus

Journal article
Authors Katarina Truvé
P. Dickinson
A. Q. Xiong
D. York
K. Jayashankar
G. Pielberg
M. Koltookian
E. Muren
H. H. Fuxelius
H. Weishaupt
F. J. Swartling
G. Andersson
A. Hedhammar
E. Bongcam-Rudloff
K. Forsberg-Nilsson
D. Bannasch
K. Lindblad-Toh
Published in Plos Genetics
Volume 12
Issue 5
Pages e1006000
ISSN 1553-7404
Publication year 2016
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages e1006000
Language en
Keywords central-nervous-system, microglial activation, p2x(7) receptor, primary, brain, pdgfr-alpha, tumors, expression, domestication, model, astrocytomas, Genetics & Heredity
Subject categories Clinical Medicine


Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10(-8)). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.

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