A Genome-wide Association Study on the Genetic Basis of Hyperthyroidism in Domestic Cats

A genome-wide association study investigating the genetic basis of hyperthyroidism in domestic cats. P. A. Norman1, R. E. Jepson1, H. M. Syme1, M. D. Wallace1,2 and L. J. Davison1,2 1 Department of Clinical Services and Sciences, Royal Veterinary College, London, UK. 2 Dept of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. Hyperthyroidism (HTH) is the most common feline endocrine disease, affecting up to 10% of cats >10 years old. Despite its high prevalence, HTH pathogenesis is not well characterised. However, it appears to be multi-factorial with environmental, dietary and genetic risk factors. This study aimed to identify genetic regions associated with HTH risk, utilising data from a genome-wide association study (GWAS) previously investigating azotaemia and hypertension. This was feasible because >10% of participating cats developed HTH during long-term follow-up. Genotype data from the Illumina 63K DNA feline array were analysed for 872 non-purebred cats >8 years old, of which 102 developed HTH (total thyroxine [TT4] >55nmol/L or institution of treatment). This GWAS investigated HTH as a dichotomous case-control phenotype and also quantitatively by including age of onset, rate of progression and maximum TT4 value. Longitudinal data was used to confirm euthyroidism in controls (median [25th, 75th %] follow-up 217 [0, 728] days). To prevent control misclassification, a tiered approach was developed for defining euthyroidism based on last age at follow-up, and TT4 and TSH measurements. Euthyroid control groups were: most inclusive (n=770), moderately inclusive (n=527) and most strictly defined (n=423). Overall, 71 candidate variants nominally associated with feline HTH (EMP1≥1.00e-5 to EMP1≤0.0011). Notably, some variants are located in gene regions involved in signalling pathways for thyroid hormone synthesis, and others are linked to human thyroid carcinoma. This study revealed novel genetic associations with feline HTH. Fine-mapping of regions of interest and genotyping in additional cats is now being undertaken for validation.