Last month in Breeder News, we provided an overview of canine hip dysplasia (HD). This article is a continuation with more in-depth information about recent genetic discoveries. HD is a developmental disorder in which the hip joint does not fit properly into the socket, leading to joint instability, inflammation, and eventually arthritis. The condition varies in severity, with some dogs showing mild changes on radiographs and others experiencing debilitating lameness. Although HD is an inherited disease, the multifactorial and polygenetic nature presents challenges in identifying potential genetic causes. Some studies have an estimated inheritance of only 20-60%, depending on the breed. 1-3 Environmental factors, such as diet and exercise, can influence development of the disease and the severity of clinical signs.
A recent study titled “Genome wide association study in Swedish Labrador Retrievers identifies genetic loci associated with hip dysplasia and body weight” by Kieler et al has identified a gene that might be related to HD.4 The gene provides insight into how hip dysplasia develops and bring breeders one step closer to developing a tool to help produce unaffected puppies. This study also demonstrates strategies that scientists use to help solve these challenging questions.
A genome-wide association study (GWAS) is a way for scientists to find genes that might be linked to certain traits or diseases. It works by looking at the DNA of many dogs and comparing those with and without a certain condition, like hip dysplasia. Scientists look for small differences in the DNA, called genetic markers, that appear more often in the group with the condition. If a certain marker is found frequently in dogs with hip dysplasia but not in healthy dogs, it suggests that part of the DNA might be involved in causing the disease. This helps researchers and breeders understand what genes influence health and traits, leading to better breeding and treatment strategies.
Because HD can have a spectrum of severity, selecting healthy dogs or dogs with HD can be difficult. A challenge with any genetic study is identifying a well-described phenotype, which is a trait or gold standard diagnosis of a disease. For HD, standardized hip radiographs (x-rays) are the best options for predicting which dogs will develop arthritis due to HD. Multiple hip scoring systems using radiographs exist to identify various severities of HD, including OFA, PennHIP, and Fédération Cynologique Internationale (FCI). These standards entail obtaining hip radiographs to help predict which dogs will develop osteoarthritis from lax hips. Unfortunately, none of these modalities are perfect predictors of which dogs will go on to develop arthritis due to hip dysplasia, and dogs with excellent hip scores can still produce puppies with HD. For this study, the FCI standards and scoring scale were used, which has demonstrated a good correlation between their scores and the development of clinically detectable HD later in life.
A total of 209 dogs with numerical HD scores were evaluated, including 205 females and 4 males. Genetic profiles for each dog were obtained using 114,854 markers. Each marker represents a single nucleotide polymorphism (SNP) at a specific site, spanning across the genome. A single nucleotide polymorphism (SNP, pronounced “snip”) is a tiny change in DNA. DNA is made up of millions of small building blocks called nucleotides, like the letters in a book. Sometimes, a single letter in the DNA sequence is different from one dog to another. For example, most dogs might have an “A” at a certain spot, but some might have a “G” instead. This small difference is called a SNP.
SNPs can help scientists find genes linked to traits like size, coat color, or diseases. By comparing DNA from many dogs, researchers can see if certain SNPs appear more often in dogs with a condition like hip dysplasia. If they do, that SNP might be near a gene that is important for developing HD.
Using all 114,854 SNPs in the 209 dogs, researchers performed a genome-wide association study to compare SNPs in dogs with various hip scores. This analysis identified a region on chromosome 24 that was strongly linked to HD. This region contains a gene called NDRG3, which helps cells grow and respond to stress. If this gene does not work properly, it might cause problems in joint cartilage, leading to hip dysplasia. Interestingly, this gene is also linked to arthritis in humans.
Although this study shows promise, it is important to emphasize that further exploration of the NDRG3 gene is necessary to identify a specific genetic test or cause. Validation is required in a larger group of Labrador Retrievers and in other breeds to fully explore the finding. Other studies in the past showed promise, but breeders are still waiting for a useful tool. A previous genetic test for HD based on a previous study in Labrador Retrievers failed to validate in a larger group of dogs.5,6 By continuing to study the genetic factors influencing hip dysplasia, researchers can work towards developing better tools to reduce the prevalence of these conditions and improve overall canine health.
References
- King, M. D. Etiopathogenesis of canine hip dysplasia, prevalence, and genetics. Vet. Clin. North Am. Small Anim. Pract. 2017;47, 753–767. https://doi.org/10.1016/j.cvsm.2017.03.001.
- Wood, J. L., Lakhani, K. H. & Rogers, K. Heritability and epidemiology of canine hip-dysplasia score and its components in Labrador retrievers in the United Kingdom. Prev. Vet. Med. 2002;55, 95–108. https://doi.org/10.1016/s0167-5877(02)00090-9.
- Wang, S. et al. Genetic correlations of hip dysplasia scores for Golden retrievers and Labrador retrievers in France Sweden and the UK. Vet. J. 2017;226, 51–56. https://doi.org/10.1016/j.tvjl.2017.07.006
- Kieler, I.N., Persson, S.M., Hagman, R. et al. Genome wide association study in Swedish Labrador retrievers identifies genetic loci associated with hip dysplasia and body weight. Sci Rep 2024;14, 6090 https://doi.org/10.1038/s41598-024-56060-y.
- Bartolome N, et al. A genetic predictive model for canine hip dysplasia: Integration of Genome Wide Association Study (GWAS) and candidate gene approaches. PLoS One. 2015;10:e0122558. doi: 10.1371/journal.pone.0122558.
- Bruun CS, Bank A, Strom A, Proschowsky HF, Fredholm M. Validation of DNA test for hip dysplasia failed in Danish Labrador Retrievers. Anim. Genet. 2020;51:617–619. doi: 10.1111/age.12951.