Genetic Studies of Immunological Diseases in Dogs and Humans

Abstract: This thesis presents genetic studies aiming at enlarging our knowledge regarding the genetic factors underlying two immune-mediated diseases, hypothyroidism and autoimmune Addison’s disease (AAD), in dogs and humans, respectively.Genetic and environmental factors are indicated to contribute to canine hypothyroidism, which can be considered a model for human Hashimoto’s thyroiditis (HT). In Paper I we performed the first genome-wide association (GWA) study of this disease in three high-risk dog breeds (Gordon Setter, Hovawart and Rhodesian Ridgeback). Using an integrated GWA and meta-analysis strategy, we identified a novel hypothyroidism risk haplotype located on chromosome 12 being shared by the three breeds. The identified haplotype, harboring three genes previously not associated with hypothyroidism, is independent of the dog leukocyte antigen region and significantly enriched across the affected dogs. In Paper II we performed a GWA study in another high-risk breed (Giant Schnauzer) and detected an associated locus located on chromosome 11 and conferring protection to hypothyroidism. After whole genome resequencing of a subset of samples with key haplotypes, we fine mapped the region of association that was subsequently screened for the presence of structural variants. We detected a putative copy number variant overlapping with the upstream region of the IFNA7 gene, which is located in a region of high genomic complexity. Remarkably, perturbed activities of type I Interferons have been extensively associated with HT and general autoimmunity.In Paper III we performed the first large-scale genetic study of human AAD, a rare autoimmune disorder characterized by dysfunction and ultimately destruction of the adrenal cortex. We resequenced 1853 immune-related genes comprising of their coding sequences, untranslated regions, as well as conserved intronic and intergenic regions in extensively characterized AAD patients and control samples, all collected in Sweden. We identified BACH2 gene as a novel risk locus associated with AAD, and we showed its independent association with isolated AAD. In addition, we confirmed the previously established AAD association with the human leukocyte antigen complex.The results of these studies will hopefully help increasing the understanding of such diseases in dogs and humans, eventually promoting their well-being.