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Abstract
Canine hip dysplasia is a common, non-congenital, complex and hereditary disorder. It can inflict severe pain via secondary osteoarthritis and lead to euthanasia. An analogous disorder exists in humans. The genetic background of hip dysplasia in both species has remained ambiguous despite rigorous studies. We aimed to investigate the genetic causes of this disorder in one of the high-risk breeds, the German Shepherd. We performed genetic analyses with carefully phenotyped case-control cohorts comprising 525 German Shepherds. In our genome-wide association studies we identified four suggestive loci on chromosomes 1 and 9. Targeted resequencing of the two loci on chromosome 9 from 24 affected and 24 control German Shepherds revealed deletions of variable sizes in a putative enhancer element of the NOG gene. NOG encodes for noggin, a well-described bone morphogenetic protein inhibitor affecting multiple developmental processes, including joint development. The deletion was associated with the healthy controls and mildly dysplastic dogs suggesting a protective role against canine hip dysplasia. Two enhancer variants displayed a decreased activity in a dual luciferase reporter assay. Our study identifies novel loci and candidate genes for canine hip dysplasia, with potential regulatory variants in the NOG gene. Further research is warranted to elucidate how the identified variants affect the expression of noggin in canine hips, and what the potential effects of the other identified loci are.
Highlights
Many hereditary disorders appear in both humans and dogs with gene variants from common ancestral genes affecting the disease [1]
We used the genotypes of 525 German Shepherds with carefully determined hip scores to identify genomic regions potentially harboring genetic risk factors for the disorder
We found four regions on chromosomes 1 and 9 exhibiting suggestive association with the disorder phenotypes
Summary
Many hereditary disorders appear in both humans and dogs with gene variants from common ancestral genes affecting the disease [1]. Canine hip dysplasia (CHD) is a non-congenital disease, causing skeletal abnormalities in growing dogs, the first signs appearing at the age of three to four months [2]. The femoral head is not completely covered by the acetabulum, which leads to increased force over smaller surface area due to incongruence of the coxofemoral joint [2,3]. This in turn causes microfractures in the acetabulum and the femoral head [2,3], detrition of the articular cartilage, inflammation of the synovial membrane and secondary osteoarthritis (OA) [3]. The adolescent hip dysplasia is clinically and developmentally closest to CHD [5]
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