PRESENTATION ABSTRACTS
been documented, highlighting the relevance of comprehensive genetic screening across breeds. Three disease-associated variants were discovered in non-pedigreed cats only. To investigate the causality of nine disease-associated variants in cats of different breed backgrounds our veterinar- ians conducted owner interviews, reviewed clinical records and invited cats to follow-up clinical examinations. We also discuss AB blood group and appearance-associated genetic variation. This study represents the first comprehensive exploration of informative variants in felines by screening over 10,000 pedigreed cats. The results qualitatively contribute to the understanding of feline variant heritage and demonstrate the clinical utility and importance of such information in support- ing breeding programs and the research community. The work highlights the crucial commitment of cat breeders and registries in supporting the establishment of large genomic databases, that when combined with phenotype information can advance scientific understanding and provide insights that can be applied to improve the health and welfare of cats. #18 Genome wide Association Study of Invasive Urinary Carcinoma (iUC) in Shetland Sheepdogs and related herding breeds Heidi G. Parker 1 , Deepika Dhawan 2 , Alex C. Harris 1 , Deborah W. Knapp 2,3 , Elaine A. Ostrander 1 hgparker@mail.nih.gov 1 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA, 3 Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA Invasive urothelial carcinoma accounts for ~2% of all tumors in the dog, affecting more than 50,000 dogs each year. The disease mirrors human iUC in presentation, pathology, response to chemother- apy and presence of basal and luminal subtypes. In addition, the majority of canine and human iUC tumors harbor mutations in mTOR pathway genes. Though iUC can occur in any breed of dog, there are breeds that are at increased risk. Among those affected are the Shetland Sheepdogs that are diagnosed with iUC >5 times more frequently than the average dog. GWAS of 50 affected and 50 unaffected Shetland sheepdogs reveals association with a locus on chr13 with p=2x10-7. Shetland sheepdogs are the only high-risk breed within in the UK herding clade, however when we combine data from affected and unaffected dogs of additional breeds within the clade we see association across all breeds with p=5x10-10 after correcting for population stratification. This suggests that there is an ancestral mutation within this clade that predisposes individuals to iUC and frequency of the mutation determines the level of risk. Analysis of WGS from 11 Shetland Sheepdogs highlights a coding mutation in a magnesium trans- porter transcript that segregates with the disease. The mutation is predicted to be deleterious by both CHASM and MutPred2 and a possible cancer driver by VEST. The transporter is upregulated in many tumor types and has been shown to be regulated by members of the mTOR pathway. It has also been associated with uric acid levels which have been associated with higher risk of cancers of the urinary tract including bladder cancer. Experiments are currently underway to ascertain the frequency and pathogenicity of the mutation and to determine its role in developing iUC in dogs.
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