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Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 5, e1003475- p.Article in journal (Refereed) Published
Abstract [en]

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

Place, publisher, year, edition, pages
2013. Vol. 9, no 5, e1003475- p.
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-205345DOI: 10.1371/journal.pgen.1003475ISI: 000320030000005OAI: oai:DiVA.org:uu-205345DiVA: diva2:641424
Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2016-05-24Bibliographically approved
In thesis
1. Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
Open this publication in new window or tab >>Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents genetic studies of atopic dermatitis (AD) and IgA deficiency in dogs.

AD is a chronic inflammatory and pruritic skin disorder caused by allergic reactions against environmental allergens. Both genetic and environmental factors are involved in the development of Canine AD (CAD) and human AD. In Paper I, we performed genome-wide association studies (GWAS) and identified a locus on chromosome 27 significantly associated with CAD in German shepherd dogs (GSDs). The locus contains several genes and fine-mapping indicated strongest association close to the candidate gene PKP2. In Paper II, we performed additional fine-mapping and identified four highly associated SNPs located in regions with transcriptional regulatory potential in epithelial and immune cells. The risk alleles were associated with increased transcriptional activity and the effect on expression was cell-type dependent. These data indicate that multiple cell-type specific enhancers regulate the expression of PKP2, and/or the neighboring genes YARS2, DNM1L and FGD4, and predispose GSDs to CAD.

IgA deficiency is the most common primary immune deficiency disorder in both humans and dogs, characterized by a higher risk of recurrent mucosal tract infections, allergic and other immune-mediated diseases. In Paper III, we performed the widest screening (to date) of serum IgA levels in dog breeds (Ndogs=1267, Nbreeds=22) and defined eight breeds as predisposed to low IgA levels. In Paper IV, we performed GWAS in four of the breeds defined as prone to low IgA levels. We used a novel percentile groups-approach to establish breed-specific cut-offs to perform analyses in a close to continuous manner. In total, 35 genomic loci were suggestively associated (p<0.0005) to IgA levels, and three genomic regions (including the genes KIRREL3 and SERPINA9) were genome-wide significantly associated with IgA levels in GSDs. A ~20kb long haplotype on chromosome 28, significantly associated to IgA levels in Shar-Pei dogs, was positioned within the first intron of the gene SLIT1 overlapping with a possible dog domestication sweep.

This thesis suggests novel candidate genes involved in two immune-mediated disorders in the dog. Hopefully, these results will become an important resource for the genetic research of the corresponding human diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 88 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1128
GWAS, canine model, genetic association, immunogenetics, atopic dermatitis, IgA deficiency
National Category
Medical Genetics
Research subject
Molecular Genetics
urn:nbn:se:uu:diva-259606 (URN)978-91-554-9304-2 (ISBN)
Public defence
2015-10-06, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2015-09-11 Created: 2015-08-10 Last updated: 2015-10-01

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Tengvall, KatarinaFarias, Fabiana H. G.Pielberg, GerliCarlborg, ÖrjanLindblad-Toh, Kerstin
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