Identification of Candidate Genes for Recurrent Exertional Rhabdomyolysis in Thoroughbreds and Standardbreds

5-10% of Thoroughbred (TB) and 6% of Standardbred (STDB) racehorses suffer from painful cramping and muscle damage following exercise (recurrent exertional rhabdomyolysis [RER]). Gender, temperament, diet, and activity level influence expression of the clinical phenotype, and heritability ranges from 0.34-0.42% in TBs and 0.39-0.45% in STDBs. The objective of this project is to identify variants associated with RER. In both breeds, total phenotypic variance is explained by <1% of the SNPs tested. These SNPs were further partitioned based on estimated effect sizes. In the TB, SNPs of small, moderate, and large effect account for 45%, 35%, and 20% of the phenotypic variance, respectively. Similarly, in STDBs, small, moderate, and large effect SNPs explain 47%, 30%, and 23% variance, respectively. Genome-wide association studies (GWAS) identified seven genomic regions of interest (ROIs) significantly associated with RER in TB (n=491) and STDB (n=476) horses: two in TBs, four in STDBs, and one shared locus. Of the 274 genes within these ROIs, 34 were computationally predicted to be candidate genes for rhabdomyolysis in humans. Variants in each ROI were identified using whole genome sequences from 10 RER and 10 controls in each breed. 189,610 total variants were discovered in the ROIs, with an average of 7.5 variants per kb. Of these variants, 47.5% were within genes, and 1.1% had putative functional effects. Variants will be prioritized based on segregation between RER and control horses and predicted functional effect. High-priority variants will be used to create an assay for genotyping in the entire GWAS population.