Novel protective and risk loci in hip dysplasia in German Shepherds

Lea I Mikkola, Saila Holopainen, Anu K Lappalainen, Tiina Pessa-Morikawa, Thomas J P Augustine, Meharji Arumilli, Marjo K Hytönen, Osmo Hakosalo, Hannes Lohi and Antti Iivanainen

PLOS Genetics, 2019, vol. 15, issue 7, 1-30

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.Author summary: Hip dysplasia is a common orthopedic disorder in dogs and humans. It can pose a serious welfare problem with severe pain. The genetic background of this disorder remains inconclusive even after years of arduous research. 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. Further analysis of the identified loci on chromosome 9 by sequencing 48 dogs revealed deletions in a potential regulatory region of NOG - the gene encoding noggin, a known regulator of joint development in mice and in humans. Using a reporter assay, we demonstrated that the deletions decrease the enhancer activity of the regulatory region and could therefore affect the expression of NOG in hips. The deletions significantly differentiate the healthy and the mild phenotypes from the moderate-to-severe phenotypes. Therefore, our results suggest that the deletion protects against hip dysplasia. Future research should focus on how these regulatory variants affect the expression of noggin in canine hips, and what the roles of noggin and the other revealed loci are in canine hip dysplasia.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1008197

DOI: 10.1371/journal.pgen.1008197

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