title: 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.
abstract: 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.
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.|Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Truvé
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Dickinson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Anqi
authors.initials: A
authors.lastname: Xiong
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: York
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Kartika
authors.initials: K
authors.lastname: Jayashankar
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Gerli
authors.initials: G
authors.lastname: Pielberg
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Koltookian
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Murén
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Fuxelius
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Holger
authors.initials: H
authors.lastname: Weishaupt
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik J
authors.identifier: 0000-0002-8460-4367
authors.initials: FJ
authors.lastname: Swartling
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Hedhammar
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Bongcam-Rudloff
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg-Nilsson
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Danika
authors.initials: D
authors.lastname: Bannasch
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, United States of America.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
mesh_terms: D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D039642:Eukaryotic Initiation Factors / Q000235:genetics*; D056726:Genetic Association Studies; D016678:Genome; D055106:Genome-Wide Association Study; D005838:Genotype; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*
chemical_list: D039642:Eukaryotic Initiation Factors; D058486:Receptors, Purinergic P2X7; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase