Genetic dissection of canine hip dysplasia phenotypes and osteoarthritis reveals three novel loci

Abstract

BackgroundHip dysplasia and osteoarthritis continue to be prevalent problems in veterinary and human medicine. Canine hip dysplasia is particularly problematic as it massively affects several large-sized breeds and can cause a severe impairment of the quality of life. In Finland, the complex condition is categorized to five classes from normal to severe dysplasia, but the categorization includes several sub-traits: congruity of the joint, Norberg angle, subluxation degree of the joint, shape and depth of the acetabulum, and osteoarthritis. Hip dysplasia and osteoarthritis have been proposed to have separate genetic etiologies.ResultsUsing Fédération Cynologique Internationale -standardized ventrodorsal radiographs, German shepherds were rigorously phenotyped for osteoarthritis, and for joint incongruity by Norberg angle and femoral head center position in relation to dorsal acetabular edge. The affected dogs were categorized into mild, moderate and severe dysplastic phenotypes using official hip scores. Three different genome-wide significant loci were uncovered. The strongest candidate genes for hip joint incongruity were noggin (NOG), a bone and joint developmental gene on chromosome 9, and nanos C2HC-type zinc finger 1 (NANOS1), a regulator of matrix metalloproteinase 14 (MMP14) on chromosome 28. Osteoarthritis mapped to a long intergenic region on chromosome 1, between genes encoding for NADPH oxidase 3 (NOX3), an intriguing candidate for articular cartilage degradation, and AT-rich interactive domain 1B (ARID1B) that has been previously linked to joint laxity.ConclusionsOur findings highlight the complexity of canine hip dysplasia phenotypes. In particular, the results of this study point to the potential involvement of specific and partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderate-to-severe dysplasia and osteoarthritis of canine hip joints. Further studies should unravel the unique and common mechanisms for the various sub-traits.

Prevalence of canine hip dysplasia in 10 breeds in France, a retrospective study of the 1997-2017 radiographic screening period

“…There is a great deal of research based on genomics and DNA testing related to canine HD [38,39,40,41], some of which is linked to similar human pathology [42]. It is beyond the scope of this study to address this very specific research area, but it is likely that, in the foreseeable future, new tools will complement radiographic examination of the coxo-femoral joint in order to prevent canine HD.…”

An across-breed validation study of 46 genetic markers in canine hip dysplasia

“…Interestingly, searching the STRING database with the 12 neddylation pathway associated candidate genes from the current study (Table 3 ) and with 14 genes ( CYBA, MAPK14, MMP2, MMP9, NCF1, NCF2, NCF4, NOX3, NOXA1, NTN1, RAC1, RAC1, TRIO, VCAM1 ) highlighted in our previous studies on CHD on German Shepherds [ 13 , 40 ] produced two gene clusters that shared 12 genes associated with Class I MHC mediated antigen processing & presentation (R-CFA-983169, https://version-11-0b.string-db.org/cgi/network?networkId=bPwtieGk6WuV , and Additional file 5 ).…”

Genome-wide association studies for canine hip dysplasia in single and multiple populations – implications and potential novel risk loci

“…Direct overlaps (shared SNPs) were only found between the FCI and case-control approaches for the Finnish population (on Chr 1) and between the FCI approach in the Finnish and meta-analysis GWAS (on Chr 9). Repeating the GWAS for the Finnish population [ 11 ] with altered phenotypes, regions with suggestive associations to CHD were detected on Chr 1 (45.1–46.6 Mbp) and on Chr 9 (31.3–36.8 Mbp). For the UK population, in addition to the genome-wide significant region on Chr 21, a region with suggestive association to FCI was detected on Chr 7 (58.5–58.8 Mbp).…”

“…In a previous genome-wide association study (GWAS) on CHD and hip osteoarthritis in 721 dogs from eight breeds, SNPs associated with CHD were detected, suggesting several positional candidate genes [ 3 ]. Other studies using GWAS for CHD have not detected consistent genomic positions of quantitative trait loci (QTL) [ 4 , 8 – 11 ], which might be explained by differing features across studies, including sample sizes, the CHD-related trait used as phenotype and population structure, in addition to different breeds. Merging CHD records and genotype data across countries might improve the statistical power of GWAS by increasing the currently limited sample size of genotyped animals within countries.…”

“…In the current study, we combined CHD phenotype and genotype data from British and Swedish German Shepherd dogs (GSDs) with publicly available data from a Finnish GSD population [ 11 ] to study the genetic architecture of CHD. We performed both single-population genome-wide association studies (GWAS) and a meta-analysis (GWAS across populations), with two aims: (I) to compare the consistency of results from different datasets and the performance of different phenotype classifications and (II) to identify potential novel loci influencing CHD by utilising multiple populations.…”