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Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex

Nature Genetics volume 42, pages 250–254 (2010)Cite this article

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Abstract

The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive1,2, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies1,3. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)–related disease complex that includes both antinuclear antibody (ANA)–positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.

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Figure 1: Genome-wide association identified five loci associated with a canine SLE-related disease.
Figure 2: Fine mapping and validation of three risk loci for ANA-positive IMRD.
Figure 3: The Cfa32 locus confers risk to multiple subphenotypes.
Figure 4: The products of four of the candidate genes are involved in T-cell activation through the NF-AT pathway.

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Acknowledgements

We thank all the dog owners, breeders and veterinarians and the breed clubs of NSDTRs that have provided dog samples and are supporting this study. We thank L. Andersson for comments on the manuscript and U. Gustafson for assistance with DNA extraction. The work was supported by FORMAS, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Foundation of Thure F. and Karin Forsberg, the Swedish Kennel Club, the Swedish Nova Scotia Duck Tolling Retriever Club, AKC Canine Health Foundation, UC-Davis Center for Companion Animal Health, the Sigrid Juselius Foundation, Biocentrum Helsinki, the Academy of Finland and the Jane and Aatos Erkko Foundation, and part of the work was funded by research grants from L. Peltonen and the Center of Excellence of Complex Disease Genetics of the Academy of Finland. K.L.-T. is the recipient of a EURYI award from the European Science Foundation. A.H. was partially supported by a fellowship from the Morris Animal Foundation.

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Author notes

  1. Päivi Jokinen and Katarina Truvé: These authors contributed equally to the manuscript.

  2. Helene Hansson-Hamlin, Hannes Lohi and Kerstin Lindblad-Toh: These authors jointly directed the work.

Authors and Affiliations

  1. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Biomedical Centre, Uppsala, Sweden

    Maria Wilbe, Katarina Truvé & Göran Andersson

  2. Department of Veterinary Biosciences, Department of Medical Genetics, Program in Molecular Medicine, Folkhälsan Institute of Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    Päivi Jokinen, Eija H Seppala & Hannes Lohi

  3. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Elinor K Karlsson, Tara Biagi & Kerstin Lindblad-Toh

  4. FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA

    Elinor K Karlsson

  5. Department of Animal Science, University of California, Davis, California, USA

    Angela Hughes

  6. Department of Population Health and Reproduction, University of California, Davis, School of Veterinary Medicine, Davis, California, USA

    Danika Bannasch

  7. Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden

    Helene Hansson-Hamlin

  8. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden

    Kerstin Lindblad-Toh

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Contributions

K.L.-T., H.H.-H., G.A. and H.L. conceived the study. H.H.-H., H.L., M.W., P.J., D.B. and A.H. were responsible for collection of field material. H.H.-H. was responsible for phenotypic characterization of the field material. K.L.-T. was responsible for designing the GWA and fine-mapping experiments with input from H.L., G.A. and M.W. M.W., K.T., P.J. and E.H.S. were responsible for the GWA analysis. M.W., T.B. and E.K.K. carried out the fine-mapping analysis. K.L.-T. directed the study with input from H.H.-H., G.A. and H.L. K.L.-T., M.W., K.T. and G.A. were responsible for preparation of the manuscript with input from the other authors.

Corresponding author

Correspondence to Kerstin Lindblad-Toh.

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The authors declare no competing financial interests.

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Supplementary Table 1 and Supplementary Figures 1 and 2 (PDF 565 kb)

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Wilbe, M., Jokinen, P., Truvé, K. et al. Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat Genet 42, 250–254 (2010). https://doi.org/10.1038/ng.525

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