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

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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.

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References

  • 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 75:223–230

    Article  PubMed  CAS  Google Scholar 

  • Aulchenko YS, Ripke S, Isaacs A, van Duijn CM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics 23:1294–1296

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • 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 66:1881–1890

    Article  PubMed  CAS  Google Scholar 

  • Bieker JJ (2001) Krüppel-like factors: three fingers in many pies. J Biol Chem 276:34355–34358

    Article  PubMed  CAS  Google Scholar 

  • Cailliez F (1983) The analytical solution of the additive constant problem. Psychometrika 48:305–308

    Article  Google Scholar 

  • 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 226:749–761

    Article  PubMed  CAS  Google Scholar 

  • 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 41:8–15

    Article  PubMed  Google Scholar 

  • Cox TF, Cox MAA (1994) Multidimensional scaling. Chapman and Hall, London

    Google Scholar 

  • 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 67:1156–1162

    Article  PubMed  Google Scholar 

  • 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 18:739–747

    Article  PubMed  CAS  Google Scholar 

  • Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics, 4th edn. Pearson Education Limited, Malaysia

    Google Scholar 

  • 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 296:2225–2229

    Article  PubMed  CAS  Google Scholar 

  • Gilmour AR, Gogel BJ, Cullis BR, Thompson R (2009) ASReml User Guide Release 3.0. VSN International Ltd., Hemel Hempstead

    Google Scholar 

  • Göring HHH, Terwilliger JD, Blangero J (2001) Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet 69:1357–1369

    Article  PubMed  Google Scholar 

  • 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 203:101–104

    PubMed  Google Scholar 

  • Hamann H, Distl O (2008) Genetic variability in Hanoverian warmblood horses using pedigree analysis. J Anim Sci 86:1503–1513

    Article  PubMed  CAS  Google Scholar 

  • Henderson CR (1975) Best linear unbiased estimation and prediction under a selection model. Biometrics 31:423–447

    Article  PubMed  CAS  Google Scholar 

  • Iles MM (2008) What can genome-wide association studies tell us about the genetics of common disease? PLoS Genet 4:e33

    Article  PubMed  Google Scholar 

  • 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 71:427–434

    Google Scholar 

  • Jorgensen B, Arnbjerg J, Aaslyng M (1995) Pathological and radiological investigations on osteochondrosis in pigs, associated with leg weakness. J Vet Med Ser A 42:489–504

    Article  CAS  Google Scholar 

  • Komm K (2010) Fine mapping of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horses. PhD thesis, University of Veterinary Medicine, Hannover

  • 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 63:186–193

    Article  PubMed  CAS  Google Scholar 

  • Lampe V (2009) Fine mapping of quantitative trait loci (QTL) for osteochondrosis in Hanoverian warmblood horses. PhD thesis, University of Veterinary Medicine, Hannover

  • 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 76:155–165

    CAS  Google Scholar 

  • 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 89:167–177

    Article  PubMed  CAS  Google Scholar 

  • 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 58:89–98

    PubMed  CAS  Google Scholar 

  • 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 41:111–120

    Article  PubMed  Google Scholar 

  • 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 9:356–369

    Article  PubMed  CAS  Google Scholar 

  • McIlwraith CW (1993) Inferences from referred clinical cases of osteochondritis dissecans. Equine Vet J 25:27–30

    Article  Google Scholar 

  • 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 1:200–210

    Article  Google Scholar 

  • McIlwraith CW (2004) Developmental orthopaedic disease: problems of limbs in young horses. J Equine Vet Sci 24:475–479

    Article  Google Scholar 

  • 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 23–33

  • 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 1155–1164

    Google Scholar 

  • 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 56:202–209

    Article  PubMed  CAS  Google Scholar 

  • Olivier A, Nurton JP, Guthrie AJ (1997) An epizoological study of wastage in Thoroughbred racehorses in Gauteng, South Africa. J S Afr Vet Assoc 68:125–129

    PubMed  CAS  Google Scholar 

  • 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 25:38–41

    Article  Google Scholar 

  • Pieramati C, Pepe M, Silvestrelli M, Bolla A (2003) Heritability estimation of osteochondrosis dissecans in Maremmano horses. Livestock Prod Sci 79:249–255

    Article  Google Scholar 

  • Purcell S (2009) PLINK (v1.07). http://pngu.mgh.harvard.edu/purcell/plink/

  • 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 81:559–575

    Google Scholar 

  • Rossdale PD, Hopes R, Digby NJ, Offord K (1985) Epidemiological study of wastage among racehorses, 1982 and 1983. Vet Rec 116:66–69

    Article  PubMed  CAS  Google Scholar 

  • 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 70:425–434

    Article  PubMed  Google Scholar 

  • 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 22:288–289

    Article  PubMed  CAS  Google Scholar 

  • 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 28:3967–3978

    Article  PubMed  CAS  Google Scholar 

  • 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)

  • 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/)

  • 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

  • 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 41:11–16

    Article  PubMed  Google Scholar 

  • 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 87:1906–1912

    Article  PubMed  Google Scholar 

  • 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 31:26–30

    Article  Google Scholar 

  • 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 326:865–867

    Article  PubMed  CAS  Google Scholar 

  • Wang WYS, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6:109–118

    Article  PubMed  CAS  Google Scholar 

  • 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 53:531–539

    Article  CAS  Google Scholar 

  • 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 124:302–307

    Article  PubMed  CAS  Google Scholar 

  • 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 38:350–357

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76–82

    Article  PubMed  CAS  Google Scholar 

  • Ytrehus B, Carlson CS, Ekman S (2007) Etiology and pathogenesis of osteochondrosis. Vet Pathol Online 44:429–448

    Article  CAS  Google Scholar 

  • 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 315:2568–2580

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

LJC thanks A. Tenesa and R. Pong-Wong for helpful discussions and S. Miller for help with data preparation. LJC also thanks two anonymous referees for their helpful comments. Samples from OCD cases and controls were provided by LRB. LJC, JAW, and S. C. Bishop are financially supported by the British Equestrian Federation, the Biosciences Knowledge Transfer Network, and the Biotechnology and Biological Sciences Research Council (BBSRC). S. C. Blott, JES, CS, LYF-C, MH, TDHP and the genotyping were funded by the Horserace Betting Levy Board and the Thoroughbred Breeders’ Association.

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Corbin, L.J., Blott, S.C., Swinburne, J.E. et al. A genome-wide association study of osteochondritis dissecans in the Thoroughbred. Mamm Genome 23, 294–303 (2012). https://doi.org/10.1007/s00335-011-9363-1

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