Genome-wide association analysis in West Highland White Terriers with atopic dermatitis

Background: Atopic dermatitis (AD) is a common disease of dogs and humans. In both species, the interplay of genetic and environmental factors affect disease expression. In dogs with AD, differences in the breed studied and in their geographical origin have led to heterogeneity in genetic association and while different loci have been identified, a causative genetic mutation has not. We hypothesized that AD could be mapped in a large cohort of rigorously phenotyped, geographically restricted West Highland White Terriers (WHWT), a breed with a high prevalence of the disease. Objectives: A) Collect phenotypes and DNA from a large cohort of WHWT born in the USA. B) Perform a genome-wide association study (GWAS) for AD in these dogs to identify associated regions and genes of interest. C) Sequence genes of interest to identify pathologic variants. Methods: We collected DNA from 96 WHWT with AD and 87 controls from the same breed. DNA was isolated and dogs were genotyped using the Illumina CanineHD BeadChip. A GWAS was performed using EMMAX and associated regions were examined for genes of interest. Genes with possible relevance to AD were examined more closely in two affected and two normal WHWT using next-generation sequencing. Variants in these genes that were unique to the two affected WHWT were compared to a database of variants derived from whole genome sequencing of 200 non-WHWT dogs across 33 additional breeds. Results: The GWAS identified a 2.7 Mb genomic region on CFA3 that included 37 genes. There was a missense variant in the F2R gene in both affected dogs but this variant was also found in 35 dogs in 9 breeds in the database of whole genome sequences for whom the phenotype regarding atopic dermatitis was unknown. Conclusions: Atopic dermatitis in WHWT is associated with a region on CFA3 that contains several candidate genes. Of these, a homozygous variant in the F2R gene present in multiple breeds that also suffer from AD warrants further evaluation.