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Background Patellar luxation is an orthopedic disorder in which the patella moves out of its normal location within the femoral trochlea of the knee and it can lead to osteoarthritis, lameness, and pain. In dogs it is a heritable trait, with both environmental and genetic factors contributing to the phenotype. The prevalence of patellar luxation in the Dutch Flat-Coated Retriever population is 24%. In this study, we investigated the molecular genetics of the disorder in this population. Results Genome-wide association analysis of 15,823 single nucleotide polymorphisms (SNPs) in 45 cases and 40 controls revealed that patellar luxation was significantly associated with a region on chromosome CFA07, and possibly with regions on CFA03, CFA31, and CFA36. The exons of the genes in these regions, 0.5 Mb combined, were analyzed further. These exons from 15 cases and a pooled sample from 15 controls were enriched using custom genomic hybridization arrays and analyzed by massive parallel DNA sequencing. In total 7257 variations were detected. Subsequently, a selection of 144 of these SNPs were genotyped in 95 Flat-Coated Retrievers. Nine SNPs, in eight genes on CFA07 and CFA31, were associated with patellar luxation (P <10-4). Genotyping of these SNPs in samples from a variety of breeds revealed that the disease-associated allele of one synonymous SNP in a pseudogene of FMO6 was unique to Flat-Coated Retrievers. Conclusion Genome-wide association analysis followed by targeted DNA sequencing identified loci on chromosomes 7 and 31 as being involved in patellar luxation in the Flat-Coated Retriever breed.

Hereditary developmental orthopaedic diseases pose a serious threat to the quality of life of dogs. The pain as well as the detrimental effect on mobility that can accompany these disorders have a major impact on the dogs as well as their owners. The studies described in this thesis aim to give more insight into the incidence of the most relevant of these diseases, as well as a better understanding of how they develop. This knowledge is crucial in order to devise and maintain effective screening and breeding programs. Between 2002 and 2010 more than 35,000 Dutch purebred dogs were officially screened for hip dysplasia, elbow dysplasia or both. The frequency of hip dysplasia was 15%, and 9% for elbow dysplasia, with substantial differences between breeds. Breeds that were screened most often were the Labrador retriever, Golden Retriever, Bernese Mountain dog and Newfoundland. In these four breeds heritabilities, genetic and residual correlations, and sex predispositions were calculated for these two traits. The breeding progress made using the current selection methods was slight to moderate for hip and elbow dysplasia. Multiple primary diseases are included in the term elbow dysplasia, with fragmented coronoid process being the most frequent form. The phenotypic and genetic correlations between signs of osteoarthritis in certain locations in the elbow joint were calculated and the best radiographic indicator for these traits was determined. Between 1990 and 2007, 3834 Dutch Flat-Coated Retrievers were screened for patellar luxation, 24% of which were affected. A clear sex predisposition was observed with 30% of females affected and only 17% of males. The heritability was 0.17 in this population, indicating that environmental effects have a large impact on the development of this disorder. Breeding progress was initially high, with a reduction of incidence form 28% to 18%, but has stagnated in later years. For both hip dysplasia and patellar luxation, a genome wide a

Background: Patellar luxation is an orthopedic disorder in which the patella moves out of its normal location within the femoral trochlea of the knee and it can lead to osteoarthritis, lameness, and pain. In dogs it is a heritable trait, with both environmental and genetic factors contributing to the phenotype. The prevalence of patellar luxation in the Dutch Flat-Coated Retriever population is 24%. In this study, we investigated the molecular genetics of the disorder in this population. Results: Genome-wide association analysis of 15,823 single nucleotide polymorphisms (SNPs) in 45 cases and 40 controls revealed that patellar luxation was significantly associated with a region on chromosome CFA07, and possibly with regions on CFA03, CFA31, and CFA36. The exons of the genes in these regions, 0.5 Mb combined, were analyzed further. These exons from 15 cases and a pooled sample from 15 controls were enriched using custom genomic hybridization arrays and analyzed by massive parallel DNA sequencing. In total 7257 variations were detected. Subsequently, a selection of 144 of these SNPs were genotyped in 95 Flat-Coated Retrievers. Nine SNPs, in eight genes on CFA07 and CFA31, were associated with patellar luxation (P <10(-4)). Genotyping of these SNPs in samples from a variety of breeds revealed that the disease-associated allele of one synonymous SNP in a pseudogene of FMO6 was unique to Flat-Coated Retrievers. Conclusion: Genome-wide association analysis followed by targeted DNA sequencing identified loci on chromosomes 7 and 31 as being involved in patellar luxation in the Flat-Coated Retriever breed.

Canine Hip dysplasia (CHD) is a progressive disorder of the canine hip which consists of a genetic and environmental component. For this study the evaluations of the radiographic images of 23096 dogs originating from 38 different breeds, and officially evaluated since 2002, were collected. Based on these evaluations the prevalence of CHD in these breeds in The Netherlands has been determined and compared with [revalences as reported in international literature. The difference in prevalence of CHD in the period 1996-2002 and 2003-2009 has been determined for each breed. This difference appeared to be significantly reduced for 7 of the evaluated breeds, determined by using a Chi2-test. When comparing the breeding policy of these breeds to the breeding policy of breeds that didn’t show any improvement, it showed that in only two breeds positive HD (grade C) was accepted for breeding. In the other 5 breeds, breeding with HD positive dogs was not permitted. In the five most evaluated breeds the influence of gender on prevalence of CHD showed significance in 3 breeds. This may be a result of the uneven distribution of the gender or the difference in age at the time of evaluation between the genders. Less than 7% of all born animals are used in breeding. This creates a bottleneck which has to be kept in mind when creating breeding policies. Ways to lower the prevalence of CHD besides excluding animals with CHD from breeding, could be screening of the majority of the population, progeny research and import of disease-free breeding material.

Canine Hip dysplasia (CHD) is a progressive disorder of the canine hip which consists of a genetic and environmental component. For this study the evaluations of the radiographic images of 23096 dogs originating from 38 different breeds, and officially evaluated since 2002, were collected. Based on these evaluations the prevalence of CHD in these breeds in The Netherlands has been determined and compared with [revalences as reported in international literature. The difference in prevalence of CHD in the period 1996-2002 and 2003-2009 has been determined for each breed. This difference appeared to be significantly reduced for 7 of the evaluated breeds, determined by using a Chi2-test. When comparing the breeding policy of these breeds to the breeding policy of breeds that didn’t show any improvement, it showed that in only two breeds positive HD (grade C) was accepted for breeding. In the other 5 breeds, breeding with HD positive dogs was not permitted. In the five most evaluated breeds the influence of gender on prevalence of CHD showed significance in 3 breeds. This may be a result of the uneven distribution of the gender or the difference in age at the time of evaluation between the genders. Less than 7% of all born animals are used in breeding. This creates a bottleneck which has to be kept in mind when creating breeding policies. Ways to lower the prevalence of CHD besides excluding animals with CHD from breeding, could be screening of the majority of the population, progeny research and import of disease-free breeding material.