Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.


  1. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

    Article  CAS  Google Scholar 

  2. Sutter, N.B. et al. Extensive and breed-specific linkage disequilibrium in Canis familiaris. Genome Res. 14, 2388–2396 (2004).

    Article  CAS  Google Scholar 

  3. Karlsson, E.K. et al. Efficient mapping of mendelian traits in dogs through genome-wide association. Nat. Genet. 39, 1321–1328 (2007).

    Article  CAS  Google Scholar 

  4. Redman, J. Steroid-responsive meningitis-arteritis in the Nova Scotia duck tolling retriever. Vet. Rec. 151, 712 (2002).

    PubMed  Google Scholar 

  5. Anfinsen, K.P. et al. A retrospective epidemiological study of clinical signs and familial predisposition associated with aseptic meningitis in the Norwegian population of Nova Scotia duck tolling retrievers born 1994–2003. Can. J. Vet. Res. 72, 350–355 (2008).

    PubMed  PubMed Central  Google Scholar 

  6. Hansson-Hamlin, H. & Lilliehook, I. A possible systemic rheumatic disorder in the Nova Scotia duck tolling retriever. Acta Vet. Scand. 51, 16 (2009).

    Article  Google Scholar 

  7. Strang, A. & MacMillan, G. The Nova Scotia Duck Tolling Retriever (Alpine Publications, Loveland, Colorado, USA, 1996).

  8. Mariani, S.M. Genes and autoimmune diseases—a complex inheritance. MedGenMed 6, 18 (2004).

    PubMed  PubMed Central  Google Scholar 

  9. Tan, E.M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).

    Article  CAS  Google Scholar 

  10. Koskenmies, S. et al. Clinical and laboratory characteristics of Finnish lupus erythematosus patients with cutaneous manifestations. Lupus 17, 337–347 (2008).

    Article  CAS  Google Scholar 

  11. Wilbe, M. et al. MHC class II polymorphism is associated with a canine SLE-related disease complex. Immunogenetics 61, 557–564 (2009).

    Article  CAS  Google Scholar 

  12. Fernando, M.M. et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 4, e1000024 (2008).

    Article  Google Scholar 

  13. Karlsson, E.K. & Lindblad-Toh, K. Leader of the pack: gene mapping in dogs and other model organisms. Nat. Rev. Genet. 9, 713–725 (2008).

    Article  CAS  Google Scholar 

  14. Drögemuller, C. et al. A mutation in hairless dogs implicates FOXI3 in ectodermal development. Science 321, 1462 (2008).

    Article  Google Scholar 

  15. Salmon Hillbertz, N.H. et al. Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat. Genet. 39, 1318–1320 (2007).

    Article  CAS  Google Scholar 

  16. Wiik, A.C. et al. A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund. Genome Res. 18, 1415–1421 (2008).

    Article  CAS  Google Scholar 

  17. Kozyrev, S.V. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 40, 211–216 (2008).

    Article  CAS  Google Scholar 

  18. Guerini, D. Calcineurin: not just a simple protein phosphatase. Biochem. Biophys. Res. Commun. 235, 271–275 (1997).

    Article  CAS  Google Scholar 

  19. Olsen, N.J., Moore, J.H. & Aune, T.M. Gene expression signatures for autoimmune disease in peripheral blood mononuclear cells. Arthritis Res. Ther. 6, 120–128 (2004).

    Article  CAS  Google Scholar 

  20. Clipstone, N.A. & Crabtree, G.R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697 (1992).

    Article  CAS  Google Scholar 

  21. Kyttaris, V.C., Wang, Y., Juang, Y.T., Weinstein, A. & Tsokos, G.C. Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. J. Immunol. 178, 1960–1966 (2007).

    Article  CAS  Google Scholar 

  22. Serfling, E. et al. NFAT transcription factors in control of peripheral T cell tolerance. Eur. J. Immunol. 36, 2837–2843 (2006).

    Article  CAS  Google Scholar 

  23. Huang, G.N. et al. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319, 476–481 (2008).

    Article  CAS  Google Scholar 

  24. Chung, S.A. & Criswell, L.A. PTPN22: its role in SLE and autoimmunity. Autoimmunity 40, 582–590 (2007).

    Article  CAS  Google Scholar 

  25. Han, S., Williams, S. & Mustelin, T. Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling. Eur. J. Immunol. 30, 1318–1325 (2000).

    Article  CAS  Google Scholar 

  26. Marshall, A.J. et al. A novel B lymphocyte-associated adaptor protein, Bam32, regulates antigen receptor signaling downstream of phosphatidylinositol 3-kinase. J. Exp. Med. 191, 1319–1332 (2000).

    Article  CAS  Google Scholar 

  27. Sommers, C.L. et al. Bam32: a novel mediator of Erk activation in T cells. Int. Immunol. 20, 811–818 (2008).

    Article  CAS  Google Scholar 

  28. Lipsky, P.E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat. Immunol. 2, 764–766 (2001).

    Article  CAS  Google Scholar 

  29. Hansson-Hamlin, H., Lilliehook, I. & Trowald-Wigh, G. Subgroups of canine antinuclear antibodies in relation to laboratory and clinical findings in immune-mediated disease. Vet. Clin. Pathol. 35, 397–404 (2006).

    Article  Google Scholar 

  30. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing