title: Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours.
abstract: Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maja L
authors.initials: ML
authors.lastname: Arendt
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Melin
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tonomura
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Koltookian
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Celine
authors.initials: C
authors.lastname: Courtay-Cahen
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Netty
authors.initials: N
authors.lastname: Flindall
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bass
authors.affiliation: Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Boerkamp
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Megquir
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Youell
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Sue
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Colleen
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Department of Veterinary Clinical Sciences Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Cheryl
authors.initials: C
authors.lastname: London
authors.affiliation: Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands.|Veterinary Specialist Center De Wagenrenk, Wageningen, The Netherlands.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Rutteman
authors.affiliation: Animal Health Trust, Newmarket, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Starkey
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D034801:Mastocytoma / Q000235:genetics / Q000662:veterinary*; D020641:Polymorphism, Single Nucleotide
chemical_list: D051960:GTP-Binding Protein alpha Subunit, Gi2