Mammalian Genome

, Volume 23, Issue 3–4, pp 294–303

A genome-wide association study of osteochondritis dissecans in the Thoroughbred

  • Laura J. Corbin
  • Sarah C. Blott
  • June E. Swinburne
  • Charlene Sibbons
  • Laura Y. Fox-Clipsham
  • Maud Helwegen
  • Tim D. H. Parkin
  • J. Richard Newton
  • Lawrence R. Bramlage
  • C. Wayne McIlwraith
  • Stephen C. Bishop
  • John A. Woolliams
  • Mark Vaudin
Article

Abstract

Osteochondrosis is a developmental orthopaedic disease that occurs in horses, other livestock species, companion animal species, and humans. The principal aim of this study was to identify quantitative trait loci (QTL) associated with osteochondritis dissecans (OCD) in the Thoroughbred using a genome-wide association study. A secondary objective was to test the effect of previously identified QTL in the current population. Over 300 horses, classified as cases or controls according to clinical findings, were genotyped for the Illumina Equine SNP50 BeadChip. An animal model was first implemented in order to adjust each horse’s phenotypic status for average relatedness among horses and other potentially confounding factors which were present in the data. The genome-wide association test was then conducted on the residuals from the animal model. A single SNP on chromosome 3 was found to be associated with OCD at a genome-wide level of significance, as determined by permutation. According to the current sequence annotation, the SNP is located in an intergenic region of the genome. The effects of 24 SNPs, representing QTL previously identified in a sample of Hanoverian Warmblood horses, were tested directly in the animal model. When fitted alongside the significant SNP on ECA3, two of these SNPs were found to be associated with OCD. Confirmation of the putative QTL identified on ECA3 requires validation in an independent sample. The results of this study suggest that a significant challenge faced by equine researchers is the generation of sufficiently large data sets to effectively study complex diseases such as osteochondrosis.

Supplementary material

335_2011_9363_MOESM1_ESM.doc (34 kb)
Supplementary material 1 (DOC 34 kb)
335_2011_9363_MOESM2_ESM.doc (40 kb)
Supplementary material 2 (DOC 40 kb)
335_2011_9363_MOESM3_ESM.doc (29 kb)
Supplementary material 3 (DOC 29 kb)
335_2011_9363_MOESM4_ESM.doc (56 kb)
Supplementary material 4 (DOC 56 kb)
335_2011_9363_MOESM5_ESM.doc (52 kb)
Supplementary material 5 (DOC 52 kb)

References

  1. Andersson-Eklund L, Uhlhorn H, Lundeheim N, Dalin G, Andersson L (2000) Mapping quantitative trait loci for principal components of bone measurements and osteochondrosis scores in a wild boar x Large White intercross. Genet Res 75:223–230PubMedCrossRefGoogle Scholar
  2. Aulchenko YS, Ripke S, Isaacs A, van Duijn CM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics 23:1294–1296PubMedCrossRefGoogle Scholar
  3. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  4. Bertone AL, Bramlage LR, McIlwraith CW, Malemud CL (2005) Comparison of proteoglycan and collagen in articular cartilage of horses with naturally developing ostechondrosis and healing osteochondral fragments of experimentally induced fractures. Am J Vet Res 66:1881–1890PubMedCrossRefGoogle Scholar
  5. Bieker JJ (2001) Krüppel-like factors: three fingers in many pies. J Biol Chem 276:34355–34358PubMedCrossRefGoogle Scholar
  6. Cailliez F (1983) The analytical solution of the additive constant problem. Psychometrika 48:305–308CrossRefGoogle Scholar
  7. Clarkin CE, Allen S, Kuiper NJ, Wheeler BT, Wheeler-Jones CP, Pitsillides AA (2011) Regulation of UDP-glucose dehydrogenase is sufficient to modulate hyaluronan production and release, control sulfated GAG synthesis, and promote chondrogenesis. J Cell Physiol 226:749–761PubMedCrossRefGoogle Scholar
  8. Corbin LJ, Blott SC, Swinburne JE, Vaudin M, Bishop SC, Woolliams JA (2010) Linkage disequilibrium and historical effective population size in the Thoroughbred horse. Anim Genet 41:8–15PubMedCrossRefGoogle Scholar
  9. Cox TF, Cox MAA (1994) Multidimensional scaling. Chapman and Hall, LondonGoogle Scholar
  10. de Grauw JC, Brama PA, Wiemer P, Brommer H, van de Lest CA, van Weeren PR (2006) Cartilage-derived biomarkers and lipid mediators of inflammation in horses with osteochondritis dissecans of the distal intermediate ridge of the tibia. Am J Vet Res 67:1156–1162PubMedCrossRefGoogle Scholar
  11. Dierks C, Lohring K, Lampe V, Wittwer C, Drogemuller C, Distl O (2007) Genome-wide search for markers associated with osteochondrosis in Hanoverian warmblood horses. Mamm Genome 18:739–747PubMedCrossRefGoogle Scholar
  12. Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics, 4th edn. Pearson Education Limited, MalaysiaGoogle Scholar
  13. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229PubMedCrossRefGoogle Scholar
  14. Gilmour AR, Gogel BJ, Cullis BR, Thompson R (2009) ASReml User Guide Release 3.0. VSN International Ltd., Hemel HempsteadGoogle Scholar
  15. Göring HHH, Terwilliger JD, Blangero J (2001) Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet 69:1357–1369PubMedCrossRefGoogle Scholar
  16. Grøndahl AM, Dolvik NI (1993) Heritability estimation of osteochondrosis in the tibiotarsal joint and of bony fragments in the palmar/plantar portion of the metacarpo- and metatarsophalangeal joints of horses. J Am Vet Med Assoc 203:101–104PubMedGoogle Scholar
  17. Hamann H, Distl O (2008) Genetic variability in Hanoverian warmblood horses using pedigree analysis. J Anim Sci 86:1503–1513PubMedCrossRefGoogle Scholar
  18. Henderson CR (1975) Best linear unbiased estimation and prediction under a selection model. Biometrics 31:423–447PubMedCrossRefGoogle Scholar
  19. Iles MM (2008) What can genome-wide association studies tell us about the genetics of common disease? PLoS Genet 4:e33PubMedCrossRefGoogle Scholar
  20. Jorgensen B, Andersen S (2000) Genetic parameters for osteochondrosis in Danish Landrace and Yorkshire boars and correlations with leg weakness and production traits. Anim Sci 71:427–434Google Scholar
  21. Jorgensen B, Arnbjerg J, Aaslyng M (1995) Pathological and radiological investigations on osteochondrosis in pigs, associated with leg weakness. J Vet Med Ser A 42:489–504CrossRefGoogle Scholar
  22. Komm K (2010) Fine mapping of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horses. PhD thesis, University of Veterinary Medicine, HannoverGoogle Scholar
  23. Kuroki K, Cook JL, Tomlinson JL, Kreeger JM (2002) In vitro characterization of chondrocytes isolated from naturally occurring osteochondrosis lesions of the humeral head of dogs. Am J Vet Res 63:186–193PubMedCrossRefGoogle Scholar
  24. Lampe V (2009) Fine mapping of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horses. PhD thesis, University of Veterinary Medicine, HannoverGoogle Scholar
  25. Lee GJ, Archibald AL, Garth GB, Law AS, Nicholson D, Barr A, Haley CS (2003) Detection of quantitative trait loci for locomotion and osteochondrosis-related traits in Large White x Meishan pigs. Anim Sci 76:155–165Google Scholar
  26. Lepeule J, Bareille N, Robert C, Ezanno P, Valette JP, Jacquet S, Blanchard G, Denoix JM, Seegers H (2009) Association of growth, feeding practices and exercise conditions with the prevalence of Developmental Orthopaedic Disease in limbs of French foals at weaning. Prev Vet Med 89:167–177PubMedCrossRefGoogle Scholar
  27. Lillich JD, Bertone AL, Malemud CJ, Weisbrode SE, Ruggles AJ, Stevenson S (1997) Biochemical, histochemical, and immunohistochemical characterization of distal tibial osteochondrosis in horses. Am J Vet Res 58:89–98PubMedGoogle Scholar
  28. Lykkjen S, Dolvik NI, McCue ME, Rendahl AK, Mickelson JR, Roed KH (2010) Genome-wide association analysis of osteochondrosis of the tibiotarsal joint in Norwegian Standardbred trotters. Anim Genet 41:111–120PubMedCrossRefGoogle Scholar
  29. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JPA, Hirschhorn JN (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9:356–369PubMedCrossRefGoogle Scholar
  30. McIlwraith CW (1993) Inferences from referred clinical cases of osteochondritis dissecans. Equine Vet J 25:27–30CrossRefGoogle Scholar
  31. McIlwraith CW (2002) Arthroscopic surgery for osteochondral chip fragments and other lesions not requiring internal fixation in the carpal and fetlock joints of the equine athlete: what have we learned in 20 years? Clin Tech Equine Pract 1:200–210CrossRefGoogle Scholar
  32. McIlwraith CW (2004) Developmental orthopaedic disease: problems of limbs in young horses. J Equine Vet Sci 24:475–479CrossRefGoogle Scholar
  33. McIlwraith CW (2010) Recent advances in diagnosis of equine joint disease. In: Proceedings of the 17th Kentucky equine research nutrition conference. Kentucky Equine Research, Versailles, KY, pp 23–33Google Scholar
  34. McIlwraith CW (2011) Lameness in the young horse: osteochondrosis. In: Baxter GM (ed) Adams and Stashak’s Lameness in Horses. Iowa Sate University Press, Ames, pp 1155–1164Google Scholar
  35. Oliver LJ, Baird DK, Baird AN, Moore GE (2008) Prevalence and distribution of radiographically evident lesions on repository films in the hock and stifle joints of yearling Thoroughbred horses in New Zealand. N Z Vet J 56:202–209PubMedCrossRefGoogle Scholar
  36. Olivier A, Nurton JP, Guthrie AJ (1997) An epizoological study of wastage in Thoroughbred racehorses in Gauteng, South Africa. J S Afr Vet Assoc 68:125–129PubMedGoogle Scholar
  37. Philipsson J, Andréasson E, Sandgren B, Dalin G, Carlsten J (1993) Osteochondrosis in the tarsocrural joint and osteochondral fragments in the fetlock joints in Standardbred trotters. II. Heritability. Equine Vet J 25:38–41CrossRefGoogle Scholar
  38. Pieramati C, Pepe M, Silvestrelli M, Bolla A (2003) Heritability estimation of osteochondrosis dissecans in Maremmano horses. Livestock Prod Sci 79:249–255CrossRefGoogle Scholar
  39. Purcell S (2009) PLINK (v1.07). http://pngu.mgh.harvard.edu/purcell/plink/
  40. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 81:559–575Google Scholar
  41. Rossdale PD, Hopes R, Digby NJ, Offord K (1985) Epidemiological study of wastage among racehorses, 1982 and 1983. Vet Rec 116:66–69PubMedCrossRefGoogle Scholar
  42. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434PubMedCrossRefGoogle Scholar
  43. Schougaard H, Ronne JF, Phillipson J (1990) A radiographic survey of tibiotarsal osteochondrosis in a selected population of trotting horses in Denmark and its possible genetic significance. Equine Vet J 22:288–289PubMedCrossRefGoogle Scholar
  44. Sue N, Jack BHA, Eaton SA, Pearson RCM, Funnell APW, Turner J, Czolij R, Denyer G, Bao S, Molero-Navajas JC, Perkins A, Fujiwara Y, Orkin SH, Bell-Anderson K, Crossley M (2008) Targeted disruption of the basic Kruppel-like factor gene (Klf3) reveals a role in adipogenesis. Mol Cell Biol 28:3967–3978PubMedCrossRefGoogle Scholar
  45. R Development Core Team (2009) R: a language and environment for statistical computing (v2.10.0). Vienna, Austria: R Foundation for Statistical Computing (http://www.R-project.org)
  46. Teyssèdre S, Dupuis MC, Elsen JM, Guérin G, Schibler L, Denoix JM, Ricard A (2010) Genome-wide SNP association study identifies region of interest associated with osteochondrosis in French Trotters. In: Proceedings of the 9th world congress on genetics applied to livestock production, Leipzig, Germany, 1–6 August 2010 (http://www.kongressband.de/wcgalp2010/)
  47. Teyssèdre S, Dupuis MC, Guérin G, Schibler L, Denoix JM, Elsen JM, Ricard A (2011) Genome-wide association studies for osteochondrosis in French Trotters. J Anim Sci. doi:10.2527/jas.2011-4031
  48. van Grevenhof EM, Ducro B, Weeren P, Tartwijk J, Belt A, Bijma P (2009a) Prevalence of various radiographic manifestations of osteochondrosis and their correlations between and within joints in Dutch Warmblood horses. Equine Vet J 41:11–16PubMedCrossRefGoogle Scholar
  49. van Grevenhof EM, Schurink A, Ducro BJ, van Weeren PR, van Tartwijk JMFM, Bijma P, van Arendonk JAM (2009b) Genetic variables of various manifestations of osteochondrosis and their correlations between and within joints in Dutch warmblood horses. J Anim Sci 87:1906–1912PubMedCrossRefGoogle Scholar
  50. van Weeren PR, Sloet vO-O, Barneveld A (1999) The influence of birth weight, rate of weight gain and final achieved height and sex on the development of osteochondrotic lesions in a population of genetically predisposed Warmblood foals. Equine Vet J 31:26–30CrossRefGoogle Scholar
  51. Wade CM, Giulotto E, Sigurdsson S, Zoli M, Gnerre S, Imsland F, Lear TL, Adelson DL, Bailey E, Bellone RR, Blocker H, Distl O, Edgar RC, Garber M, Leeb T, Mauceli E, MacLeod JN, Penedo MCT, Raison JM, Sharpe T, Vogel J, Andersson L, Antczak DF, Biagi T, Binns MM, Chowdhary BP, Coleman SJ, la Valle G, Fryc S, Guerin G, Hasegawa T, Hill EW, Jurka J, Kiialainen A, Lindgren G, Liu J, Magnani E, Mickelson JR, Murray J, Nergadze SG, Onofrio R, Pedroni S, Piras MF, Raudsepp T, Rocchi M, Roed KH, Ryder OA, Searle S, Skow L, Swinburne JE, Syvanen AC, Tozaki T, Valberg SJ, Vaudin M, White JR, Zody MC, Broad Institute Genome Sequencing Platform, Broad Institute Whole Genome Sequencing Assembly Team, Lander ES, Lindblad-Toh K (2009) Genome sequence, comparative analysis, and population genetics of the domestic horse. Science 326:865–867PubMedCrossRefGoogle Scholar
  52. Wang WYS, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6:109–118PubMedCrossRefGoogle Scholar
  53. Wittwer C, Hamann H, Rosenberger E, Distl O (2006) Prevalence of osteochondrosis in the limb joints of South German Coldblood horses. J Vet Med Series A Physiol Pathol Clin Med 53:531–539CrossRefGoogle Scholar
  54. Wittwer C, Hamann H, Rosenberger E, Distl O (2007a) Genetic parameters for the prevalence of osteochondrosis in the limb joints of South German Coldblood horses. J Anim Breed Genet 124:302–307PubMedCrossRefGoogle Scholar
  55. Wittwer C, Lohring K, Drogemuller C, Hamann H, Rosenberger E, Distl O (2007b) Mapping quantitative trait loci for osteochondrosis in fetlock and hock joints and palmar/plantar osseus fragments in fetlock joints of South German Coldblood horses. Anim Genet 38:350–357PubMedCrossRefGoogle Scholar
  56. Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76–82PubMedCrossRefGoogle Scholar
  57. Ytrehus B, Carlson CS, Ekman S (2007) Etiology and pathogenesis of osteochondrosis. Vet Pathol Online 44:429–448CrossRefGoogle Scholar
  58. Zhang J, Yang C, Brey C, Rodriguez M, Oksov Y, Gaugler R, Dickstein E, Huang CH, Hashmi S (2009) Mutation in Caenorhabditis elegans Krüppel-like factor, KLF-3 results in fat accumulation and alters fatty acid composition. Exp Cell Res 315:2568–2580PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Laura J. Corbin
    • 1
  • Sarah C. Blott
    • 2
  • June E. Swinburne
    • 2
  • Charlene Sibbons
    • 2
  • Laura Y. Fox-Clipsham
    • 2
  • Maud Helwegen
    • 2
  • Tim D. H. Parkin
    • 3
  • J. Richard Newton
    • 2
  • Lawrence R. Bramlage
    • 4
  • C. Wayne McIlwraith
    • 5
  • Stephen C. Bishop
    • 1
  • John A. Woolliams
    • 1
  • Mark Vaudin
    • 2
  1. 1.The Roslin Institute and Royal (Dick) School of Veterinary StudiesUniversity of EdinburghMidlothianScotland, UK
  2. 2.Animal Health TrustNewmarketUK
  3. 3.Boyd Orr Centre for Population and Ecosystem Health, Institute of Comparative Medicine, Faculty of Veterinary MedicineUniversity of GlasgowGlasgowScotland, UK
  4. 4.Rood and Riddle Equine HospitalLexingtonUSA
  5. 5.College of Veterinary Medicine and Biomedical SciencesColorado State UniversityFort CollinsUSA

Personalised recommendations