Genome-wide investigation of hip dysplasia in dogs

Media interest has brought health-related problems in purebred dogs to the public's attention, resulting in several ongoing enquiries sponsored by the government and independent organizations. Although we do not yet know the outcome of all of these reviews, they are likely to highlight many of the same issues as those identified by the RSPCA in their recent report (2008). These include problems resulting from excessive inbreeding and from inadvertent selection for disease traits in the course of selection for other characteristics (e.g. coat patterns). A prominent health issue in pedigree dogs, particularly large breeds, is that of hip dysplasia (HD), associated with painful and disabling osteoarthritis as the dog ages. There are currently attempts to reduce this disease in some breeds by preferentially breeding from dogs with low predisposition to disease. This involves selection using hip scores, x-ray measurements of hip laxity, which are associated with HD. However, the progress of genetic change by selection on hip scores has been found to be very slow. Furthermore, these tests involve putting the dog under general anaesthesia, which raises other animal welfare issues. Recent advances in canine genomics, including the sequencing of the dog genome and the development of a high-density 'chip' for dog genetic analysis, provide an opportunity for a faster and less invasive means to genetic improvement in these traits. This project applies a genomic approach to improving HD in dogs, using the Labrador Retriever breed as a test case. The Labrador is the most common dog breed in the UK and in many other countries, and one in which rates of HD and are relatively high. Our primary objective is to look for associations between the genetic constitution of dogs and their predisposition to HD and in so doing, we will identify regions of the genome that influence this trait. Using this information, we can provide 'genomic breeding values' for each dog analyzed, this value will encompass the dog's predisposition to HD, based on its genetic make-up. We will also further characterize the most promising genetic region associated with this disease by comparing our results to those of previous studies. We will then examine the relationship between hip dysplasia and other traits, including elbow dysplasia, a related disease, and specifically test whether the same regions of the genome are associated with predisposition to both diseases. Our second objective is to develop a plan for implementation of 'genomic selection' (selection based on many genetic markers) in Labradors. The costs of genetic testing are high and much of the variation that is measured in standard tests will not be related to these traits. We will use information from the analysis to evaluate whether a subset of genetic markers is predictive of disease susceptibility. If such a set can be identified, it may be possible develop a cost-effective means of testing for HD in the Labrador, which may also be applicable to other breeds. Using computer models and the results from the genetic analyses, we will evaluate how best to design a breeding and genotyping scheme for this and other diseases.

This project exploits two novel technologies to address genetic improvement of complex, health traits in pedigree dogs: the development of dense canine SNP panels and genomic selection, a statistical approach that uses such genotype information to provide genomic breeding values for use in a selection scheme. This approach is currently being applied in dairy cattle but has not previously been used for pedigree dogs. We plan to apply this approach to predisposition to hip dysplasia (as assessed by hip score) in the Labrador Retriever, as a test case. Our primary goals are to calculate genomic breeding values and to identify genomic regions associated with hip score. To achieve this, we will genotype 1500 animals from the extremes of the phenotypic distribution in Labradors, using the Illumina 200K CanineHD array. Based on theoretical approximations and heritability estimates for this disease, we predict that this approach should result in faster selection for improved health than a traditional phenotype- and pedigree-based approach. The genomic regions identified in the study will be further analysed by comparison with results from previous QTL studies of hip dysplasia in dogs, with the aim of identifying candidate genes. We will also analyse genetic interactions between hip score and other traits, including elbow score (associated with the related disease, elbow dysplasia). Our secondary objective is to develop an implementation plan for genomic selection against hip dysplasia. This will involve identification of lower-density SNP panels that characterise maximal genetic variation for given numbers of SNPs. We will also perform a simulation study to evaluate the efficacy of alternative breeding and genotyping schemes. Several features will be evaluated for their effects on genetic progress: (1) size and breadth of the genotyping panel, (2) timing of genotyping, and (3) proportion of dogs genotyped in the breed.

The outcome of this project, with its novel approach and use of new genomic technology, will have an impact by providing underpinning science for the development of public policy related to companion animal welfare, a priority area for BBSRC. The current importance of this area to society can be gauged from the observation that there are three enquiries ongoing within the UK on genetics in relation to the welfare of pedigree dogs, sponsored by government and NGOs. The UK has a high profile in pedigree dog breeding and the use of cutting edge science to ameliorate welfare problems associated with genetics will have an international impact. Communication of the project activity and outcomes will be aided by activities of the project team in relation to the Companion Animal Welfare Council, the Kennel Club and breed clubs - both CAWC and the KC have taken steps to address this area. Dog breeders and owners: Breeders will have better tools to select for reduced risk of hip dysplasia and to differentiate their dogs from others, and may benefit from increased export of their dogs. Owners will clearly benefit from reduced emotional suffering due to the development of hip dysplasia in their pet, and from reduced financial risks associated with vet treatment. Maximising this impact depends on publicising benefits, however we already have the support of key stakeholders, such as KC and Guide Dogs for the Blind. Further, we have a communication plan for owners and breed clubs already mapped out, with meetings and publications in the appropriate popular press. The team is experienced in these communication activities. The clinical involvement within the team, and conducting the project within a veterinary school, adds an additional communication route for impact via vets who will play a major role in communicating results and promoting benefits to owners. Commercial interests: These include genome companies who supply the DNA chips, providers of genotyping services, and insurance companies. There is an existing infrastructure to provide the genomic services and the project team and their institutions enjoy strong relationships with key players in this area. Insurers of pet health would also obtain financial benefits from better management of their risk exposure, and some of this could be passed on to owners in new policy options. Organisations involved in training and working with dogs: Charities and other organizations will benefit from improved lifetime health of recruited dogs. At present, ~7% of potential guide dogs fail due to health problems, a substantial cost and loss of dogs from the programme. Scientific beneficiaries: The international reputation of the UK science base will benefit from the publication of innovative science in peer-reviewed journals, the post-doc will be provided with high-quality training in combining quantitative genetic techniques with fast developing genomic technologies at a world leading centre. Moreover the science provides the scientific platform for further study in identifying causative variants underlying developmental disorders, extending the results to other breeds, and using this project as a model for approaching other complex diseases in dogs and other managed populations. The training, policy and awareness impacts would be delivered at the end of the project. The impacts related directly to improved dog health will begin to be delivered with the first cohort of dogs born and will accumulate over generations. The size of impact will depend on the uptake and use of the technology, and our project aims to inform stakeholders on the most effective means of achieving the benefits.