Thoroughbred racehorses die on racetracks. Many of these are the result of catastrophic musculoskeletal injuries, but a proportion are the result of sudden cardiac death – the collapse and death of an apparently healthy horse. Necropsies show that in about a quarter of these cases the pathologist cannot identify cause of death: these are termed autopsy-negative, exercise-associated sudden cardiac death (AN-EASD). Significant risk factors involving the individual horse (such as age and sex) and the race itself (such as distance and purse) have been identified. Genetic predisposition also plays a role and heritability estimates have recently been calculated but no known genetic risk factors have thus far been identified. There is a critical need to identify genetic risk factors and use these in selective breeding to reduce the prevalence in the breed, and for individual horse risk assessment and prevention strategies. We have recently performed a preliminary study using 31 cases and 66 controls in which we identified an association that has a compelling candidate gene nearby. The over-arching objective of this research proposal is to identify and understand the genetic basis for AN-EASD in thoroughbred racehorses. We have two specific aims: Specific Aim 1: To validate our preliminary association by performing a genome-wide association study (GWAS) using an independent genotyped cohort. Specific Aim 2: To increase the number of variants up to genome-wide level by using imputation on the genotype array panels and merging these into one dataset. This merged imputed dataset will be used to perform GWAS and to identify candidate causal variants along with whole-genome sequencing. We have put together a strong team of collaborators, representing three departments of CVM, including an anatomic pathologist, an equine geneticist, a bioinformatician, and a veterinary geneticist with extensive collaborative expertise. Our findings have important implications for the racing industry, including jockey safety and racehorse welfare.