Genome-wide investigation of hip dysplasia in dogs

Lead Research Organisation: University of Edinburgh
Department Name: The Roslin Institute

Abstract

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.

Technical Summary

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.

Planned Impact

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 (CAWC), the Kennel Club (KC) 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 publicizing 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 postdoc 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.

Publications

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Friedrich J (2018) Accuracy of genotype imputation in Labrador Retrievers. in Animal genetics

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Lofgren S (2014) Management and personality in Labrador Retriever dogs in Applied Animal Behaviour Science

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Sanchez Molano, E (2013) Genomic prediction for susceptibility to hip dysplasia in Labrador retrievers in The 7th international conference on advances in canine and feline genomics and inherited diseases

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Sánchez-Molano E (2014) Assessing the impact of genomic selection against hip dysplasia in the Labrador Retriever dog. in Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie

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Sánchez-Molano E (2015) Genomic prediction of traits related to canine hip dysplasia. in Frontiers in genetics

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Wiener P (2015) Dissecting genetic and non-genetic influences on dog personality in Journal of Veterinary Behavior

 
Description In collaboration with The Animal Health Trust (Newmarket, England), we are collaborating on a study of the genetics of hip dysplasia and other traits in Labrador retrievers. We had a terrific response from dog owners and breeders, and characterized almost 1200 dogs for more than 180,000 DNA markers covering the dog genome, allowing us to identify regions of the genome influencing this disease. Two genome-wide and several chromosome-wide QTLs affecting CHD and its related traits were identified, indicating regions related to hip dysplasia, however these regions explained only a small proportion of the variation for the traits. Thus, consistent with previous studies, the genetic architecture of CHD appears to be based on many genes with small or moderate effect, suggesting that genomic selection rather than marker-assisted selection may be an appropriate strategy for reducing this disease. We followed up the genetic association analyses by using statistical techniques and computer simulations to assess the potential impact of genomic selection against hip dysplasia, in which markers from across the genome are used to predict a dog's predisposition to the disease. We found that genomic selection would be a promising alternative to pedigree-based selection against CHD, however, more phenotypes with genomic data are required to improve further the accuracy of prediction.
Exploitation Route We are continuing to try to expand a genomic and phenotypic dataset that will facilitate a genomic approach to selection against canine hip dysplasia in dogs. Most recently, we have explored the possibility of pooling data from different countries and dog breeds. We will be investigating this further in a new project investigating hip dysplasia in German Shepherd dogs.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Canine Welfare Grant
Amount £198,540 (GBP)
Organisation Dogs Trust 
Sector Charity/Non Profit
Country Unknown
Start 09/2015 
End 02/2018
 
Description Dogs Trust Welfare Grant
Amount £55,092 (GBP)
Organisation Dogs Trust 
Sector Charity/Non Profit
Country Unknown
Start 04/2019 
End 03/2020
 
Description SRUC: genetic and environmental dissection of behavioural traits 
Organisation Scotland's Rural College
Country United Kingdom 
Sector Academic/University 
PI Contribution We are managing a study of genetic and non-genetic factors associated with behaviour in dogs, incorporating data collection, analysis and interpretation. Funded by the Dogs Trust, we are employing a postdoctoral researcher to carry out the research.
Collaborator Contribution They provide expertise in animal behaviour and are collaborating on data collection, analysis and interpretation.
Impact Several publications have resulted from this collaboration and further funding has been secured. This multi-disciplinary collaboration involves genetics and animal behaviour.
Start Year 2012
 
Description Midlothian Science Festival Dog Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Spoke to a number of dog owners about our work on genetics of complex traits in dogs, which sparked questions and discussion.
Year(s) Of Engagement Activity 2016
 
Description Presentation of research at Crufts dog show 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact With a number of colleagues, we were able to both share our research findings and to hear concerns from dog owners and breeders about dog health.
Year(s) Of Engagement Activity 2015
 
Description Presentation of research at Royal Highland Show 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact We presented research findings and spoke to a large number of animal breeders and other visitors to the Show.
Year(s) Of Engagement Activity 2014