Novel protective and risk loci in hip dysplasia in German Shepherds

PLoS Genet. 2019 Jul 19;15(7):e1008197. doi: 10.1371/journal.pgen.1008197. eCollection 2019 Jul.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • Chromosome Mapping
  • Chromosomes, Mammalian / genetics
  • Dogs
  • Enhancer Elements, Genetic
  • Genetic Testing / veterinary
  • Genome-Wide Association Study / veterinary*
  • Hip Dysplasia, Canine / genetics*
  • Sequence Analysis, DNA / veterinary
  • Sequence Deletion

Substances

  • Carrier Proteins
  • noggin protein

Associated data

  • figshare/10.6084/m9.figshare.8231456

Grant support

This study was funded by The Academy of Finland (252602, www.aka.fi, to AI), The American Kennel Club Canine Health Foundation (01828, www.akcchf.org, to AI), The Jane and Aatos Erkko Foundation (jaes.fi/en, to HL) and Biocentrum Helsinki (to HL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.