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Novel protective and risk loci in hip dysplasia in German Shepherds.
PLoS Genet 2019; 15(7):e1008197PG

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.

Authors+Show Affiliations

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31323019

Citation

Mikkola, Lea I., et al. "Novel Protective and Risk Loci in Hip Dysplasia in German Shepherds." PLoS Genetics, vol. 15, no. 7, 2019, pp. e1008197.
Mikkola LI, Holopainen S, Lappalainen AK, et al. Novel protective and risk loci in hip dysplasia in German Shepherds. PLoS Genet. 2019;15(7):e1008197.
Mikkola, L. I., Holopainen, S., Lappalainen, A. K., Pessa-Morikawa, T., Augustine, T. J. P., Arumilli, M., ... Iivanainen, A. (2019). Novel protective and risk loci in hip dysplasia in German Shepherds. PLoS Genetics, 15(7), pp. e1008197. doi:10.1371/journal.pgen.1008197.
Mikkola LI, et al. Novel Protective and Risk Loci in Hip Dysplasia in German Shepherds. PLoS Genet. 2019;15(7):e1008197. PubMed PMID: 31323019.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel protective and risk loci in hip dysplasia in German Shepherds. AU - Mikkola,Lea I, AU - Holopainen,Saila, AU - Lappalainen,Anu K, AU - Pessa-Morikawa,Tiina, AU - Augustine,Thomas J P, AU - Arumilli,Meharji, AU - Hytönen,Marjo K, AU - Hakosalo,Osmo, AU - Lohi,Hannes, AU - Iivanainen,Antti, Y1 - 2019/07/19/ PY - 2018/05/01/received PY - 2019/05/14/accepted PY - 2019/07/31/revised PY - 2019/7/20/pubmed PY - 2019/7/20/medline PY - 2019/7/20/entrez SP - e1008197 EP - e1008197 JF - PLoS genetics JO - PLoS Genet. VL - 15 IS - 7 N2 - 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. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/31323019/Novel_protective_and_risk_loci_in_hip_dysplasia_in_German_Shepherds L2 - http://dx.plos.org/10.1371/journal.pgen.1008197 DB - PRIME DP - Unbound Medicine ER -