title: Identification and validation of risk loci for osteochondrosis in standardbreds.
abstract: BACKGROUND
  Osteochondrosis (OC), simply defined as a failure of endochondral ossification, is a complex disease with both genetic and environmental risk factors that is commonly diagnosed in young horses, as well as other domestic species. Although up to 50 % of the risk for developing OC is reportedly inherited, specific genes and alleles underlying risk are thus far completely unknown. Regions of the genome identified as associated with OC vary across studies in different populations of horses. In this study, we used a cohort of Standardbred horses from the U.S. (n = 182) specifically selected for a shared early environment (to reduce confounding factors) to identify regions of the genome associated with tarsal OC. Subsequently, putative risk variants within these regions were evaluated in both the discovery population and an independently sampled validation population of Norwegian Standardbreds (n = 139) with tarsal OC.
  
  
  RESULTS
  After genome-wide association analysis of imputed data with information from >200,000 single nucleotide polymorphisms, two regions on equine chromosome 14 were associated with OC in the discovery cohort. Variant discovery in these and 30 additional regions of interest (including 11 from other published studies) was performed via whole-genome sequencing. 240 putative risk variants from 10 chromosomes were subsequently genotyped in both the discovery and validation cohorts. After correction for population structure, gait (trot or pace) and sex, the variants most highly associated with OC status in both populations were located within the chromosome 14 regions of association.
  
  
  CONCLUSIONS
  The association of putative risk alleles from within the same regions with disease status in two independent populations of Standardbreds suggest that these are true risk loci in this breed, although population-specific risk factors may still exist. Evaluation of these loci in other populations will help determine if they are specific to the Standardbred breed, or to tarsal OC or are universal risk loci for OC. Further work is needed to identify the specific variants underlying OC risk within these loci. This is the first step towards the long-term goal of constructing a genetic risk model for OC that allows for genetic testing and quantification of risk in individuals.
authors.affiliation: Veterinary Population Medicine Department, University of Minnesota, 1365 Gortner Ave., St. Paul, MN, USA. mccoya@illinois.edu.|Department of Veterinary Clinical Medicine, University of Illinois, 1008 Hazelwood Dr., Urbana, IL, USA. mccoya@illinois.edu.
authors.forename: Annette M
authors.initials: AM
authors.lastname: McCoy
authors.affiliation: Veterinary Population Medicine Department, University of Minnesota, 1365 Gortner Ave., St. Paul, MN, USA. beeso018@umn.edu.
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Beeson
authors.affiliation: Department of Animal and Poultry Sciences, Virginia Tech, 3470 Litton Reaves Hall, Blacksburg, VA, USA. rsplan@vt.edu.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Splan
authors.affiliation: Faculty of Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, NMBU-School of Veterinary Science, P.O. Box 8146 Dep., Oslo, Norway. sigrid.lykkjen@nmbu.no.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Lykkjen
authors.affiliation: School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, 84 Lipman Dr., New Brunswick, NJ, USA. ralstonvmd@msn.com.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Ralston
authors.affiliation: Veterinary Biological Sciences Department, University of Minnesota, 1988 Fitch Ave., St. Paul, MN, USA. micke001@umn.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Mickelson
authors.affiliation: Veterinary Population Medicine Department, University of Minnesota, 1365 Gortner Ave., St. Paul, MN, USA. mccu0173@umn.edu.
authors.forename: Molly E
authors.initials: ME
authors.lastname: McCue
mesh_terms: D000818:Animals; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006734:Horse Diseases / Q000235:genetics* / Q000473:pathology; D006736:Horses; D055034:Osteochondrosis / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors