Genetics of hip dysplasia, elbow dysplasia and patellar luxation in purebred dogs

Abstract

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 association study was performed. For hip dysplasia 48 affected Labrador Retrievers were compared to 30 healthy ones, which resulted in significant association on chromosome 8, and suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Exons in these regions were sequenced and identified several candidate genes which might influence the development of hip dysplasia in this breed. These candidate genes, LAMA2, LRR1 and COL6A3, are involved in differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. For patellar luxation, 45 affected Flat-Coated Retrievers and 40 healthy ones were compared. Significant association was found on chromosome 7, as well as suggestive association on chromosomes 3, 31 and 36. Exons in these regions were sequenced in 15 cases and a pool of controls. More than 7,000 variations were found, 124 of which were genotyped in a cohort of 95 Flat-Coated Retrievers. Nine SNPs, in eight genes, were associated with patellar luxation.