Replication and Fine-Mapping of a QTL for Recurrent Airway Obstruction (RAO) in European Warmblood Horses

Recurrent airway obstruction (RAO) or “heaves” is a common performance limiting allergic respiratory disease of mature horses. It is related to sensitization and exposure to mouldy hay and has a familial basis with a complex mode of inheritance. In a previous study we detected a QTL for RAO on ECA 13 in a half-sib family of European Warmblood horses. In this study we genotyped additional markers in the family and narrowed the QTL down to about 1.5 Mb (23.7-25.2 Mb). We detected the strongest linkage to SNP BIEC2-224511 (24,309,405 bp). We also obtained SNP genotypes in an independent cohort of 646 unrelated Warmblood horses. There was no genome-wide significant association to RAO in these unrelated horses. However, we performed a genotypic association study of the SNPs on ECA 13 in these unrelated horses and the SNP BIEC2-224511 showed the strongest association to RAO of all markers on ECA 13 (p_raw = 0.00037). The T-allele at this SNP was associated with RAO both in the family and the unrelated horses. Thus, the association study in the unrelated animals provides independent support for the previously detected QTL. The association study allows further narrowing of the QTL interval to about 0.5 Mb (24.0-24.5 Mb). We sequenced the coding regions of the genes in the critical region but did not find any associated coding variants. Therefore, the causative variant underlying this QTL is most likely a regulatory mutation. Key words: Horse, allergy, recurrent airway obstruction, association, QTL, replication, fine-mapping