Genome Wide Association Study for Equine Exertional Rhabdomyolysis in Standardbred Horses

Recurrent exertional rhabdomyolysis (RER), a syndrome characterized by painful cramping and muscle damage with exercise, is thought to have an underlying genetic basis in Standardbred (STDB) racehorses. Our objective was to identify genomic regions contributing to RER by performing a genome-wide association study (GWAS) in a cohort of 148 STDB horses (89 cases and 59 controls). Cases were defined as horses with a history of one or more episodes of rhabdomyolysis; whereas controls had no documented rhabdomyolysis or muscle disease. Horses were genotyped for 54,602 or 65,153 single nucleotide polymorphisms (SNPs) with Illumina genotyping arrays. Genotypes were imputed to a uniform set of 74,595 SNPs with BEAGLE using genotype data from 323 additional STDB horses. Following quality control and data pruning in PLINK (Hardy-Weinberg equilibrium, missingness rates, discordant sex information and heterozygosity), 64,280 SNPs remained for analysis. A genotype-based relationship-matrix and the covariates gender, gait and sex were included in a mixed logistic regression model using Genome-wide Efficient Mixed Model Analysis (GEMMA) software. A significant association was noted across 4 SNPs spanning a 583.9 kb region on chromosome 14. Haplotype analysis across a ~1 Mb region of interest was performed using haplo.stats in R. Both sliding window and sequential haplotype analysis identified a 114 kb and a 98 kb haplotype significantly associated with RER (simulated p-values determined with label swapping permutation of ≤0.000001 to 0.00001). Based on haplotype association analysis, five cases and five control horses were submitted for whole genome sequencing and variant discovery.