Breed-specific SNP and genomic regions associated with equine recurrent exertional rhabdomyolysis susceptibility overlapping withup- and down-regulatory histone modifications

Recurrent exertional rhabdomyolysis (RER) is a myopathy characterised by episodes of exercise-induced myofibre necrosis, muscle stiffness and fasciculations, with extreme cases resulting in kidney failure or death. There is a genetic component attributed to RER1-3, but specific causative genes and mutations have not been identified. Due to the disease’s metabolic nature, we hypothesised that regulatory regions of the genome may be implicated4. We aimed to identify genetic markers for RER in Thoroughbreds (TB), Warmbloods (WB) and Connemara ponies (CP). Since many of these were located in non-coding regions we compared their location with peaks in the publicly-available equine ChIP-seq data obtained from the FAANG portal5.

33 CP (17 cases, 16 controls) and 94 WB (50 cases, 44 controls) were genotyped using a 670k genotyping array. GWAS, regional heritability mapping (RHM) and FST analyses were thenrun both across and within breeds. Various window sizes around significant and suggestive markers from these analyses, and 26 previously-identified US TB RER markers2 re-mapped to EquCab3.0, were compared to locations of histone markers identified in longissimus dorsi samples from two horses in the FAANG data using bedtools. No ChIP-seq peaks directly overlapped TB QTLs, but 6 in CPs and 2 in WBs overlapped with significant and suggestive significant SNPs for RER susceptibility. Within 10 kb of TB QTLs there were significantly fewer H3K27me3 and more H3K4me3 peaks than expected, whilst WB RHM regions contained significantly more H3K27me3 peaks and fewer H3K4me1 peaks than expected. No Bonferroni-corrected significant differences were identified in CP alone.