TY - JOUR

T1 - Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

AU - Arendt, Maja L

AU - Melin, Malin

AU - Tonomura, Noriko

AU - Koltookian, Michele

AU - Courtay-Cahen, Celine

AU - Flindall, Netty

AU - Bass, Joyce

AU - Boerkamp, Kim

AU - Megquir, Katherine

AU - Youell, Lisa

AU - Murphy, Sue

AU - McCarthy, Colleen

AU - London, Cheryl

AU - Rutteman, Gerard R

AU - Starkey, Mike

AU - Lindblad-Toh, Kerstin

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Alternative Splicing

KW - Animals

KW - Dog Diseases/genetics

KW - Dogs

KW - GTP-Binding Protein alpha Subunit, Gi2/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Germ-Line Mutation

KW - Mastocytoma/genetics

KW - Polymorphism, Single Nucleotide

U2 - 10.1371/journal.pgen.1005647

DO - 10.1371/journal.pgen.1005647

M3 - Journal article

C2 - 26588071

VL - 11

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 11

M1 - e1005647

ER -