A genome-wide association study for recurrent laryngeal neuropathy in the Thoroughbred horse identifies a candidate gene that regulates myelin structure

Abstract

Background: Equine recurrent laryngeal neuropathy (RLN) is an economically important upper respiratory tract (URT) disease with a genetic contribution to risk, but genetic variants independent of height have not been identified for Thoroughbreds. The method of clinical assessment for RLN is critical to accurately phenotype groups for genetic studies. Objectives: To identify genetic risk loci for RLN in Thoroughbreds in a genome-wide association study (GWAS) following high-resolution phenotyping. Study design: Case–control. Methods: Thoroughbred horses were characterised as RLN cases and controls using resting and exercising URT endoscopic examinations and laryngeal ultrasonography, with the case-cohort supplemented using a questionnaire. Genotypes for 43 831 autosomal single-nucleotide polymorphisms (SNPs) from n = 235 horses (n = 110 cases; n = 125 controls) were used to estimate trait heritability and identify significantly associated SNPs in a GWAS. Haplotypes were examined in cases and controls and risk allele frequencies were examined in a population cohort (n = 3126). Results: Heritability was h2 = 0.30 including sex and 5PCs as covariates. A SNP on ECA20 located between candidate genes, DAAM2 and LRFN2, was significantly associated with RLN. Six index SNPs with allelic effect sizes OR = 1.5–2.9 were identified on ECA1, ECA14, and ECA20 close to candidate genes ATPA10, KCNN2, and TFAP2A. Eleven ECA20 SNPs defined seven haplotypes with homozygous H2/H2 horses having a 3.1× higher risk of RLN. Risk alleles segregate in the population, and stallions are carriers. Main limitations: The main study population was young. Horses in the control group had no evidence of RLN as 2- or 3-year olds but may have developed RLN later. Conclusions: Genetic markers for RLN were identified which may be useful for the development of a polygenic risk score. Candidate genes with functions in neuropathies may further the understanding of RLN pathobiology.