BackgroundEquine recurrent uveitis (ERU), an inflammatory eye disease, is the leading cause of blindness among horses. Insidious uveitis, a form of ERU, is especially pervasive within the Appaloosa breed and is highly heritable (h2 = 0.68-1.0). To date only one risk locus, leopard complex (LP), has been identified, and it explained 0.16-0.33 of the heritability estimate, suggesting that insidious uveitis is a complex genetic disease within the Appaloosa horse breed with multiple unknown predisposing loci.ResultsA genome-wide association study (GWAS) using relatedness, LP genotype, sex, and age as covariates was performed on a sample of 96 Appaloosas (36 cases and 60 controls) and identified a 9.7 Kb region of association on ECA X (chrX:14528106-14537812) as significantly associated (P = 2.11 × 10-8). Sex stratification followed by meta-analysis provided additional support for the association on ECA X (P = 1.35 × 10-8). A logistic regression model was performed to test for epistasis between LP and the locus on ECA X, and the results did not support an interaction between the two loci. In the second phase of the study, single-nucleotide variants (SNVs) were identified in the region on ECA X by whole genome sequencing (WGS) of 18 horses from the GWAS (9 cases and 9 controls). Five reference markers from the GWAS, two previously associated coat color loci (LP and PATN1), and 102 SNVs were further evaluated in a combined dataset of 157 horses (70 cases and 87 controls, including the original 96 horses from the GWAS). Using logistic regression, none of the SNVs identified from the WGS analysis were significantly associated with phenotype; however, LP and the top three SNP markers from ECA X (ECA X: 14.5 Mb) were significantly associated in the larger dataset (PLP = 2.34 × 10-6 and PX = 4.06 × 10-5).ConclusionIn addition to the LP locus, our investigation identified a locus on chromosome X with a significant association to insidious uveitis in Appaloosas. Replication testing in an independent cohort is necessary to determine if this locus is indeed a causal risk locus
