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some lesions may not be visible on standard lateromedial or anterior–posterior views. Another important confounding factor is that in some studies all osteochondral fragments are counted as OC lesions, whereas others discriminate between fragments likely to be osteochondrotic in nature and those supposed to be of other origin, such as plantar/palmar osteochondral fragments (Sønnichsen et al. 1982; Dalin et al. 1993; Nixon and Pool 1995). Also, the outcome of genetic studies will depend on whether OC is defined at the animal level or at the joint level. Lastly, the methodology differs between studies. Sire models only account for paternal half-sib relationships. Animal models use information on all relatives of an animal without reduction to specific structures of relatives (Lykkjen et al. 2013, 2014). Osteochondrosis (OC) is always a categorical variable, in which case a threshold model or a transformation to the underlying distribution should be applied to avoid underestimation (J€


onsson et al. 2011). All these factors together make genetic studies on OC


difficult to interpret and even more difficult to compare between each other.


Molecular genetics There have been great advances in molecular genetics in recent decades. The basic genome of the horse was published in 2009 (Wade et al. 2009), opening the way for genome-wide association studies. Osteochondrosis was a logical candidate for this approach and the outcome of these studies gave further insight in the complexity of OC. Regions associated with some phenotypic manifestation of OC were found on no fewer than 22 of the 33 chromosomes of the horse (Dierks et al. 2006, 2007, 2010a,b; Wittwer et al. 2007; Felicetti et al. 2009; Lampe et al. 2009a,b; Lykkjen et al. 2010; Corbin et al. 2012; Orr et al. 2012; Teyss


edre et al. 2012; Distl 2013). There appeared to be


large differences with respect to these quantitative trait loci between breeds, joints and even manifestations of OC. Only two of 24 quantitative trait loci found to be associated with OC in Hanoverian Warmbloods were shown to be associated with the disease also in Thoroughbreds (Corbin et al. 2012). The phenotypic and genotypic association between OC in the tarsocrural joint and in the metacarpophalangeal/ metatarsophalangeal joints turned out to be very low, if not virtually nonexistent, in many studies (Van Grevenhof et al. 2009a,b; Lykkjen et al. 2012) and there are even indications that different manifestations of OC within the same joint (fragmentation versus flattening of the joint) may represent different traits (Van Grevenhof et al. 2009b). Hence, whilst there is uncontestably a genetic component in OC, this genetic contribution is far from straightforward.


a)


Genes involved From the molecular genetic studies, several candidate genes have emerged as potentially implicated in OC (Table 1). Many of those are not directly related to cartilage or bone metabolism, but have more general roles. A major problem with studies using material from horses with established OC is that no discrimination has been made yet between primary and secondary processes. This is very difficult to achieve, as the healing process is known to follow soon after lesion formation. This applies also to the work comparing gene expression profiles of leucocytes from horses affected by OC and normal controls. In that work dysregulation of a number of pathways in OC-affected animals was noted, among others in Wnt, Indian hedgehog (Ihh), and transforming growth factor-b signalling (Serteyn et al. 2010). Ihh is an interesting target, given its role together with parathyroid hormone-releasing peptide in the feedback loop involved in chondrogenesis (Semevolos et al. 2002). However, in another study no relation of genetic polymorphism of the Ihh gene with OC could be demonstrated in Polish Halfbreds (Zabek et al. 2013). In the pig the gene encoding T-box transcription factor 5 was shown to be associated with OC (Rangkasenee et al. 2013). This is potentially interesting as this transcription factor is involved in vascularisation, but no data on the horse exist thus far. The study by Olstad et al. (2008a) on vascular changes in the growth cartilage is probably most relevant in the quest for the genetic background of OC, as it was performed on very young foals. In that study the tousled-like kinase two gene and an unknown gene were upregulated in foals predisposed to OC (Austbø et al. 2010).


Genomic selection The genetic background of OC is clearly very complex and not easy to unravel. An important limiting factor is the lack of agreement in the definition of the phenotype. This leads inevitably to variation in outcome. It is highly unlikely that a simple genetic test comprising only few culprit genes will ever be developed for OC. This does not exclude genomic selection. Genomic selection is a possible and likely future avenue for the selection against OC in the horse. In genomic selection genome-wide single nucleotide polymorphism genotype information is combined with pedigree and phenotypic data to produce genomic estimated breeding values. In several commercial species, such as dairy livestock, genomic selection is now reality (Stock and Reents 2013). A limitation of genetic selection is that large reference populations are needed to obtain highly accurate estimated breeding values. This is relatively easy in cattle, but less so in


b)


Fig 6: a) and b) Pathological cartilage fracture (arrows) through the area of ischaemic chondronecrosis, i.e. osteochondrosis dissecans occurred in one foal examined 42 days after vessel transection (Olstad et al. 2013).


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