Identification of a Genetic locus for Immune-Mediated Myositis in Quarter Horses

Quarter Horses (QH) and related breeds develop recurrent, rapid-onset muscle atrophy as a result of immune-mediated myositis (IMM). The hallmark of IMM in muscle biopsies is the presence of lymphocytes (CD4+, CD8+, CD20+) within myocytes. The cause of IMM is unknown, although genetic and environmental influences are believed to be important factors. The purpose of this study was to determine if IMM in QHs is associated with a specific genetic locus. Based on history, clinical signs and lymphocytic infiltrates in muscle biopsies, 36 IMM QH cases (21 male, 15 female) were selected from archives of the Neuromuscular Diagnostic Laboratory. DNA was extracted from blood or muscle samples from IMM cases and from blood samples of 54 age and breed matched unaffected horses (21 male, 33 female) that were housed in the same environment as IMM cases. A genome wide association study was performed across 40,564 single nucleotide polymorphisms (SNPs) that passed quality control (genotyping >90%, minor allele frequency >99%) using the Illumina Equine 50K and 70K SNP platforms. To account for elevated genomic inflation (λGC= 1.84) a mixed model analysis was performed using GRAMMAR, decreasing genomic inflation to 0.96. Five SNPs, located within a 2 Mb window on ECA11, were significantly associated with the IMM phenotype (P_unadjusted  2.58x10^-7). Putative functional variants in the associated region are being investigated in whole genome sequences of 4 IMM and 4 unaffected horses.  Well-phenotyped IMM affected and unaffected horses from the same environment were integral to the successful mapping of an IMM genetic locus.