Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland.
PLoS Genet. 2019 Jul 19;15(7):e1008197. doi: 10.1371/journal.pgen.1008197. eCollection 2019 Jul.
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.
犬髋关节发育不良是一种常见的非先天性、复杂且遗传性疾病。它会通过继发性骨关节炎引起严重疼痛，并导致安乐死。人类也存在类似的疾病。尽管进行了严格的研究，但这两种物种髋关节发育不良的遗传背景仍不清楚。我们旨在研究高危品种之一——德国牧羊犬中这种疾病的遗传原因。我们对包含 525 只德国牧羊犬的精心表型病例对照队列进行了遗传分析。在全基因组关联研究中，我们在 1 号和 9 号染色体上确定了四个提示性位点。对来自 24 只受影响和 24 只对照德国牧羊犬的 9 号染色体上的两个位点进行靶向重测序，发现了 NOG 基因一个假定增强子元件中的大小可变的缺失。NOG 编码 noggin，这是一种众所周知的骨形态发生蛋白抑制剂，影响包括关节发育在内的多种发育过程。该缺失与健康对照犬和轻度发育不良的犬相关，表明其对犬髋关节发育不良具有保护作用。两种增强子变体在双荧光素酶报告基因检测中显示活性降低。我们的研究确定了犬髋关节发育不良的新位点和候选基因，NOG 基因中的潜在调节变体。需要进一步研究阐明所鉴定的变体如何影响犬髋关节中 noggin 的表达，以及其他鉴定出的位点的潜在影响。
