Investigations into the genetics of atopic dermatitis in guide dogs

Canine atopic dermatitis (cAD) is a common pruritic, inflammatory condition resulting from an immune response to heightened allergen sensitivity that usually manifests in the skin leading to an ‘itch-scratch’ cycle. Differential prevalence among breeds points to genetic variation in predisposition, and various environmental influences have been reported. It is the most common cause of withdrawals among in-training and working guide dogs, representing a major cost to the organisation not just from withdrawals but also in the treatment and management of affected dogs, as well as a major welfare burden on the affected dogs themselves. This study merged, validated, and utilised existing single nucleotide polymorphism (SNP) array data gathered from 347 Labrador and Labrador x Golden Retriever cross guide dogs born between 2001 and 2019 which had been collected for other collaborative research projects. Binary diagnoses of cAD were determined from health records and used as the phenotype in analysis. An additional phenotype of melanin type, which can be discerned from coat colour and which is known to be wholly determined by a point mutation at the Melanocortin 1 receptor gene on chromosome 5, was also analysed to demonstrate the legitimacy of methods and against which to compare results which may inform of aetiology. The heritability estimates of cAD ranged from 0.42 to 0.62, from analysis of breed groups separately or together, demonstrating substantial genetic variation in affectation. The heritability estimates for melanin type approached 1 as would be expected. Genome-wise association revealed 5 SNPs with an association with cAD of suggestive significance (P<10-5), but none remained after correction for multiple testing. Comparison of QQ and Manhattan plots implied a different aetiology for cAD to melanin type, comprising a large number of genes with modest association distributed across chromosomes. Clusters of SNPs of modest association with cAD revealed regions of interest, and genes located therein were compiled into a short- and longlist for functional annotation analysis. Several clusters of functional annotation terms appeared to be significantly enriched, including epidermal growth factor (EGF) domains and protein glycosylation, neurological function around the synapse, cellular differentiation, kinase mediated regulation, cellular transport/secretion, Zinc-finger transcriptional regulation, protein modification and cell membrane. Significantly enriched functional annotation terms were focussed on the EGF-like domains and Teneurins, both functionally diverse but also both involved in cell-to-cell adhesion which could impact the functionality of the skin barrier. About 40% of genes in both the long- and shortlist were indicated as being expressed in the skin, and several were good candidates based on reported function and associations. For example, the gene glucosaminyl(N-acetyl) transferase 2 (GCNT2) has a role in the transdifferentiation of epithelial cells to mesenchymal cells in injured tissues during inflammation, which could have an influence in maintenance and healing of the skin barrier. The gene striatin (STRN) is an intracellular binding protein expressed in the skin and is involved in tight cell junctions, which are known to act as the ‘seal’ between epithelial cells and have previously been reported as associated with cAD. The results from this study support and corroborate the complex aetiology of cAD. There are multiple reports of differing genes associated with cAD among different breeds and populations, but many have similar functional annotation themes, as do those reported here. These reflect the known biological processes and systems that are involved, including regulation of the cell cycle and interleukin production, protein binding and intracellular signalling, cell differentiation and cell junction, and cell membrane signalling and trafficking. The complexity of the networks of physiological processes and pathways involved which underpin the growth and formation of the skin barrier and the immune response provide ample scope for the existence of epi-genetic modification and epistatic interaction. However, given the heterogenous but heritable nature of the disease, selection represents the most viable means of reducing the prevalence of cAD among guide dogs.

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