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

PLoS Genet. 2016 May 12;12(5):e1006000. doi: 10.1371/journal.pgen.1006000. eCollection 2016 May.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / genetics*
  • Dog Diseases / genetics*
  • Dogs
  • Eukaryotic Initiation Factors / genetics*
  • Genetic Association Studies
  • Genome
  • Genome-Wide Association Study
  • Genotype
  • Glioma / genetics*
  • Glioma / pathology
  • Humans
  • Polymorphism, Single Nucleotide
  • Receptors, Purinergic P2X7 / genetics*

Substances

  • Eukaryotic Initiation Factors
  • Receptors, Purinergic P2X7
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase

Grant support

This study was partially funded by the Swedish Kennel Club, Agria Insurance Company, the Swedish Research Council, Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the EMBRACE project funded by the European Commission within its FP6 Programme, under the thematic area "Life sciences, genomics and biotechnology for health", contract number LHSG-CT-2004-512092, The University of California Cancer Research Coordinating Committee, The Center for Companion Animal Health, UC Davis School of Veterinary Medicine and by the Paul C. and Borghild T. Petersen Foundation. KLT is the recipient of a European Young Investigator Award (EURYI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.