Abstract
BackgroundEquine recurrent laryngeal neuropathy (RLN) is a bilateral mononeuropathy with an unknown pathogenesis that significantly affects performance in Thoroughbreds. A genetic contribution to the pathogenesis of RLN is suggested by the higher prevalence of the condition in offspring of RLN-affected than unaffected stallions. To better understand RLN pathogenesis and its genetic basis, we performed a genome-wide association (GWAS) of 282 RLN-affected and 268 control Thoroughbreds.ResultsWe found a significant association of RLN with the LCORL/NCAPG locus on ECA3 previously shown to affect body size in horses. Using height at the withers of 505 of these horses, we confirmed the strong association of this locus with body size, and demonstrated a significant phenotypic and genetic correlation between height and RLN grade in this cohort. Secondary genetic associations for RLN on ECA18 and X did not correlate with withers height in our cohort, but did contain candidate genes likely influencing muscle physiology and growth: myostatin (MSTN) and integral membrane protein 2A (ITM2A).ConclusionsThis linkage between body size and RLN suggests that selective breeding to reduce RLN prevalence would likely reduce adult size in this population. However, our results do not preclude the possibility of modifier loci that attenuate RLN risk without reducing size or performance, or that the RLN risk allele is distinct but tightly linked to the body size locus on ECA3. This study is both the largest body size GWAS and the largest RLN GWAS within Thoroughbred horses to date, and suggests that improved understanding of the relationship between genetics, equine growth rate, and RLN prevalence may significantly advance our understanding and management of this disease.
Highlights
Equine recurrent laryngeal neuropathy (RLN) is a bilateral mononeuropathy with an unknown pathogenesis that significantly affects performance in Thoroughbreds
Association mapping of RLN Using the full case–control dataset (550 horses: 282 cases and 268 controls) and correcting for sex and gelding, the strongest association with RLN was centered on a SNP, BIEC2_808543, adjacent to the ligand-dependent nuclear receptor corepressor-like (LCORL) and nonSMC condensing I complex, subunit G (NCAPG) genes (P = 1.1 × 10−10, Figure 1A)
The effect of the LCORL/NCAPG and chromosome 18 QTLs was consistent between males and females whereas the chromosome 23 QTL appeared stronger in females and the chromosome X QTL appeared stronger in males (Table 1)
Summary
Equine recurrent laryngeal neuropathy (RLN) is a bilateral mononeuropathy with an unknown pathogenesis that significantly affects performance in Thoroughbreds. To better understand RLN pathogenesis and its genetic basis, we performed a genome-wide association (GWAS) of 282 RLN-affected and 268 control Thoroughbreds. Equine recurrent laryngeal neuropathy ( known as idiopathic laryngeal hemiplegia) is a common upper respiratory tract disorder of horses and a significant cause of their reduced athletic performance [1]. RLN represents a distal axonopathy of the recurrent laryngeal nerves, which is clinically expressed only on the left side of the larynx. Recurrent laryngeal neuropathy is an important axonopathy for horses in competitive events, because the resultant paresis of the intrinsic laryngeal muscles leads to obstruction of air flow during intense exercise, an abnormal inspiratory noise known as “roaring,” and, most importantly, reduced performance. Even though all horses going through sales are endoscopically examined for evidence of RLN, the condition may not yet be clinically evident in some animals [7] so a diagnostic test to predict RLN risk would be very useful
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