Abstract
Equine metabolic syndrome (EMS) is a complex trait for which few genetic studies have been published. Our study objectives were to perform within breed genome-wide association analyses (GWA) to identify associated loci in two high-risk breeds, coupled with meta-analysis to identify shared and unique loci between breeds. GWA for 12 EMS traits identified 303 and 142 associated genomic regions in 264 Welsh ponies and 286 Morgan horses, respectively. Meta-analysis demonstrated that 65 GWA regions were shared across breeds. Region boundaries were defined based on a fixed-size or the breakdown of linkage disequilibrium, and prioritized if they were: shared between breeds or across traits (high priority), identified in a single GWA cohort (medium priority), or shared across traits with no SNPs reaching genome-wide significance (low priority), resulting in 56 high, 26 medium, and seven low priority regions including 1853 candidate genes in the Welsh ponies; and 39 high, eight medium, and nine low priority regions including 1167 candidate genes in the Morgans. The prioritized regions contained protein-coding genes which were functionally enriched for pathways associated with inflammation, glucose metabolism, or lipid metabolism. These data demonstrate that EMS is a polygenic trait with breed-specific risk alleles as well as those shared across breeds.
Highlights
Equine metabolic syndrome (EMS) is best described as a clustering of risk factors often leading to laminitis, which is the primary clinical concern due to the painful and often career ending outcome of this disease [1]
A dominant mode of inheritance for laminitis status was originally proposed for a small group of ponies [3], breed differences in EMS susceptibility, metabolic profiles, and clinical severity have led to the more widely applicable, alternative hypothesis that EMS is a complex disease, with both environmental and genetic risk factors contributing to disease severity
(i.e., five single nucleotide polymorphism (SNP) exceeding the suggestive threshold and one or more SNPs exceeded the threshold for genome-wide significance) and included: seven ROI for baseline insulin, one ROI for INS-OST, three ROI for baseline glucose, two ROI for GLU-OST, two ROI for NEFA, one ROI for triglycerides, two ROI for adiponectin, three ROI for leptin, three ROI for ACTH, 14 ROI for NH, 16 ROI for GH, and 10 ROI for laminitis status (Tables S1 and S2)
Summary
Equine metabolic syndrome (EMS) is best described as a clustering of risk factors often leading to laminitis, which is the primary clinical concern due to the painful and often career ending outcome of this disease [1]. A dominant mode of inheritance for laminitis status was originally proposed for a small group of ponies [3], breed differences in EMS susceptibility, metabolic profiles, and clinical severity have led to the more widely applicable, alternative hypothesis that EMS is a complex disease, with both environmental and genetic risk factors contributing to disease severity. Our laboratory provided evidence for this hypothesis through estimation of narrow sense heritability in a cohort of Morgan horses and Welsh ponies, where eight metabolic measurements were estimated to have low, moderate or high heritability [5]. Several heritability estimates varied across the two breeds, providing further evidence for breed related differences and are consistent with heritability estimates across ethnic groups for metabolic syndrome (MetS) in humans, a syndrome with shares distinct metabolic similarities to EMS
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