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

• DOI: 10.1371/journal.pgen.1006000
• Publication Date: 2016-05-12T17:38:56Z
• Authors: Katarina Truvé; Peter Dickinson; Anqi Xiong; Daniel York; Kartika Jayashankar; Gerli Pielberg; Michele Koltookian; Eva Murén; Hans-Henrik Fuxelius; Holger Weishaupt; Fredrik J. Swartling; Göran Andersson; Åke Hedhammar; Erik Bongcam-Rudloff; Karin Forsberg-Ni...; Danika Bannasch; Kerstin Lindblad-Toh
• Keywords: Candidate gene; Genome-wide Association Study; Genetic Association

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