A genome‐wide association study identifies a region strongly associated with symmetrical onychomadesis on chromosome 12 in dogs

Abstract

Symmetrical onychomadesis causes periodic loss of claws in otherwise healthy dogs. Genome-wide association analysis in 225 Gordon Setters identified a single region associated with symmetrical onychomadesis on chromosome 12 (spanning about 3.3 mb). A meta-analysis including also English Setters indicated that this genomic region predisposes for symmetrical onychomadesis in English Setters as well. The associated region spans most of the major histocompatibility complex and nearly 1 Mb downstream. Like many other autoimmune diseases, associations of symmetrical onychomadesis with DLA class II alleles have been reported. In this study, no associated markers were revealed within any of the DLA-DRB1, -DQA1 or -DQB1 genes, and the odds for symmetrical onychomadesis in the Gordon Setters were much higher, carrying significant single nucleotide polymorphisms compared to the odds of any of the recorded DLA-DRB1/DQA1/DQB1 haplotypes. We noticed that some of the associated DLA haplotypes were different between the English Setters and the Gordon Setters. Interestingly, associated SNP chip markers showed a more consistent pattern of allelic variants related to cases or controls regardless of breed. In conclusion, the associated genetic markers identified in this study hold the potential to aid in selection of breeding animals to reduce the frequency of symmetrical onychomadesis in the dog.

DLA class II risk haplotypes for autoimmune diseases in the bearded collie offer insight to autoimmunity signatures across dog breeds

“…Similar connections have been made for dogs, and review of the published literature shows that several autoimmune conditions are associated with DLA class II risk haplotypes (as shown in Table 1) [3, 24, 28, 35–45].…”

“…Furthermore, the DQ1 combination is found in two different three-locus haplotypes that have been associated with higher risk for hypothyroidism (lymphocytic thyroiditis) in Doberman pinschers, giant schnauzers (DLA-DRB1*012:01/DQA1*001:01/DQB1*002:01) and English setters (DLA-DRB1*001:07/DQA1*001:01/DQB1*002:01) [40, 43, 44]. Moreover, the four three-locus DLA class II risk haplotypes associated with SLO in different dog breeds [24, 28, 43] carry a DQ1 or DQ2 haplotype. These DQ haplotypes were also observed in two SLO-affected dogs in our database that represent breeds in which SLO is uncommon: one great dane, heterozygous for DQ1, and one Belgian tervuren, homozygous for DQ2 (unpublished finding).…”

“…DQ2 is found in haplotype 1, the risk haplotype for AD in the bearded collie and diabetes mellitus in multiple dog breeds [39]. It is also a part of haplotype 5, which is associated with risk for SLO in the bearded collie and Gordon setter [24, 28, 43], and a three-locus haplotype associated with meningoencephalitis in the greyhound (DLA-DRB1*018:02/DQA1*001:01/DQB1*008:02) [45]. These observations indicate that DQ haplotypes may constitute signatures of autoimmune predisposition across multiple dog breeds, which perhaps combine with breed-specific genetic components to determine the tissue-specificity of autoimmune disease expression.…”

“…Likely due to its role in recognition of self versus non-self, variation within MHC class II alleles has been implicated in multiple human autoimmune disorders including Addison’s disease, type 1 diabetes mellitus and inflammatory bowel disease [30, 32–34]. Similar connections have been made for dogs, and review of the published literature shows that several autoimmune conditions are associated with DLA class II risk haplotypes (as shown in Table 1) [3, 24, 28, 35–45].…”

“…Since then, most research has focused on disease diagnosis and treatment [22, 25]. While little research exists on the cause of SLO, Wilbe et al [24] and Dahlgren et al [28] have reported an association with particular major histocompatibility complex (MHC; or Dog Leukocyte Antigen, DLA) class II alleles in bearded collies, giant schnauzers, and English and Gordon setters [24, 28]. DLA class II haplotypes were also shown to be more prevalent among dogs of multiple breeds with AD [3].…”