Abstract
<title>Abstract</title> <p> Background Thoroughbred horses have been strongly selected for exercise adaptations for competitive racing. Previous genome-wide association studies (GWAS) and expression quantitative trait locus (eQTL) analyses have examined the genomic architecture underlying variation in athletic performance and the transcriptional response to exercise in skeletal muscle in Thoroughbreds. However, no study has simultaneously leveraged a transcriptome-wide association study (TWAS), colocalisation analyses, and Summary-data-based Mendelian Randomisation (SMR) framework to identify causal mechanisms underpinning phenotypic variation for athletic performance traits. Results Here, we integrate RNA-seq data generated from Thoroughbred skeletal muscle sampled across three exercise states (untrained resting, untrained post-exercise, trained resting), and GWAS results for racing distance and speed traits, and use TWAS, colocalisation and SMR methodologies to characterise functionally relevant causal genes and variants for exercise traits. Exercise and training response eQTLs (reQTLs) were enriched in metabolic and stress response processes and showed distinct genomic localisation. Genes associated with racing distance ( <italic>MSTN</italic> and <italic>ORMDL1</italic> ) and speed ( <italic>ATAT1, DHDH, GPT2</italic> , and <italic>GYS1</italic> ) were identified. Conclusion This study provides important new omics insights into the distinction between inherited and acquired molecular mechanisms that underpin the adaptive exercise and training responses of skeletal muscle and demonstrates the Thoroughbred horse’s importance as an animal model for exercise. </p>