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Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis.

Tengvall K, Kierczak M, Bergvall K, Olsson M, Frankowiack M, Farias FH, Pielberg G, Carlborg Ö, Leeb T, Andersson G, Hammarström L, Hedhammar Å, Lindblad-Toh K - PLoS Genet. (2013)

Bottom Line: Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach.The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes.Our results may yield further insight into the genetics behind both canine and human AD.

View Article: PubMed Central - PubMed

Affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. katarina.tengvall@imbim.uu.se

ABSTRACT
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 = 1.1 × 10(-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 (λ = 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 = 3.0 × 10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 × 10(-7), pgenome = 0.03). The total associated region was defined as a ~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 ~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.

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Correlation between the phenotypes and obvious population structure was detected in the GSD population.The difference in IgA levels (pdiff = 1.1×10−5, based on Welsh two sample t-test) in CAD cases and CAD controls (Ntotal = 184, before removing CAD controls with low IgA levels) is presented with boxplots (A). The GSD population is visualised with an MDS-plot displaying the formation of two subpopulations (B) with the uneven distribution of CAD cases and CAD controls (C). The distribution of IgA levels across the subpopulations is visualized with violin plots (D). Panels B-D include all dogs after QC (n = 203) and the dotted lines on the violin plots (A and D) correspond to the respective median values.
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pgen-1003475-g001: Correlation between the phenotypes and obvious population structure was detected in the GSD population.The difference in IgA levels (pdiff = 1.1×10−5, based on Welsh two sample t-test) in CAD cases and CAD controls (Ntotal = 184, before removing CAD controls with low IgA levels) is presented with boxplots (A). The GSD population is visualised with an MDS-plot displaying the formation of two subpopulations (B) with the uneven distribution of CAD cases and CAD controls (C). The distribution of IgA levels across the subpopulations is visualized with violin plots (D). Panels B-D include all dogs after QC (n = 203) and the dotted lines on the violin plots (A and D) correspond to the respective median values.

Mentions: We investigated the diagnostic features CAD and low IgA levels, in a Swedish population of GSDs. The total number of dogs included in the study is presented in Table 1. When considering the CAD phenotype we first evaluated the relationship of the following parameters; CAD status, IgA levels and gender. 40.7% (n = 37) of the CAD cases had IgA-levels ≤0.10 g/l compared to 5.4% (n = 5) of the CAD controls. The IgA levels were significantly lower in CAD cases versus controls p = 1.1×10−5 (Figure 1A), mean IgA level in cases was 0.16 g/l and 0.26 g/l in controls (before excluding the 5 CAD controls with low IgA levels from the final association analysis, see Materials and Methods). We detected no gender bias in cases versus controls for CAD (p = 0.88). When considering whether IgA levels were related to age, we determined regression coefficient of 0.42 in all dogs together (p = 3.0×10−9), 0.37 in cases (p = 3.6×10−4) and 0.28 in controls (p = 8.5×10−3). We added the age at sampling as a covariate in the association analyses in order to remove any confounding effects of the IgA measurements' dependency of age.


Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis.

Tengvall K, Kierczak M, Bergvall K, Olsson M, Frankowiack M, Farias FH, Pielberg G, Carlborg Ö, Leeb T, Andersson G, Hammarström L, Hedhammar Å, Lindblad-Toh K - PLoS Genet. (2013)

Correlation between the phenotypes and obvious population structure was detected in the GSD population.The difference in IgA levels (pdiff = 1.1×10−5, based on Welsh two sample t-test) in CAD cases and CAD controls (Ntotal = 184, before removing CAD controls with low IgA levels) is presented with boxplots (A). The GSD population is visualised with an MDS-plot displaying the formation of two subpopulations (B) with the uneven distribution of CAD cases and CAD controls (C). The distribution of IgA levels across the subpopulations is visualized with violin plots (D). Panels B-D include all dogs after QC (n = 203) and the dotted lines on the violin plots (A and D) correspond to the respective median values.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3649999&req=5

pgen-1003475-g001: Correlation between the phenotypes and obvious population structure was detected in the GSD population.The difference in IgA levels (pdiff = 1.1×10−5, based on Welsh two sample t-test) in CAD cases and CAD controls (Ntotal = 184, before removing CAD controls with low IgA levels) is presented with boxplots (A). The GSD population is visualised with an MDS-plot displaying the formation of two subpopulations (B) with the uneven distribution of CAD cases and CAD controls (C). The distribution of IgA levels across the subpopulations is visualized with violin plots (D). Panels B-D include all dogs after QC (n = 203) and the dotted lines on the violin plots (A and D) correspond to the respective median values.
Mentions: We investigated the diagnostic features CAD and low IgA levels, in a Swedish population of GSDs. The total number of dogs included in the study is presented in Table 1. When considering the CAD phenotype we first evaluated the relationship of the following parameters; CAD status, IgA levels and gender. 40.7% (n = 37) of the CAD cases had IgA-levels ≤0.10 g/l compared to 5.4% (n = 5) of the CAD controls. The IgA levels were significantly lower in CAD cases versus controls p = 1.1×10−5 (Figure 1A), mean IgA level in cases was 0.16 g/l and 0.26 g/l in controls (before excluding the 5 CAD controls with low IgA levels from the final association analysis, see Materials and Methods). We detected no gender bias in cases versus controls for CAD (p = 0.88). When considering whether IgA levels were related to age, we determined regression coefficient of 0.42 in all dogs together (p = 3.0×10−9), 0.37 in cases (p = 3.6×10−4) and 0.28 in controls (p = 8.5×10−3). We added the age at sampling as a covariate in the association analyses in order to remove any confounding effects of the IgA measurements' dependency of age.

Bottom Line: Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach.The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes.Our results may yield further insight into the genetics behind both canine and human AD.

View Article: PubMed Central - PubMed

Affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. katarina.tengvall@imbim.uu.se

ABSTRACT
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 = 1.1 × 10(-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 (λ = 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 = 3.0 × 10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 × 10(-7), pgenome = 0.03). The total associated region was defined as a ~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 ~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.

Show MeSH
Related in: MedlinePlus