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
SN - 1553-7390
VL - 11
JO - PLOS Genetics
JF - PLOS Genetics
IS - 11
M1 - e1005647
ER -