Novel protective and risk loci in hip dysplasia in German Shepherds.

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.

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

BACKGROUND: Canine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants. RESULTS: We execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Fédération Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation. CONCLUSIONS: Our study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.

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

BACKGROUND: Association mapping studies of quantitative trait loci (QTL) for canine hip dysplasia (CHD) can contribute to the understanding of the genetic background of this common and debilitating disease and might contribute to its genetic improvement. The power of association studies for CHD is limited by relatively small sample numbers for CHD records within countries, suggesting potential benefits of joining data across countries. However, this is complicated due to the use of different scoring systems across countries. In this study, we incorporated routinely assessed CHD records and genotype data of German Shepherd dogs from two countries (UK and Sweden) to perform genome-wide association studies (GWAS) within populations using different variations of CHD phenotypes. As phenotypes, dogs were either classified into cases and controls based on the Fédération Cynologique Internationale (FCI) five-level grading of the worst hip or the FCI grade was treated as an ordinal trait. In a subsequent meta-analysis, we added publicly available data from a Finnish population and performed the GWAS across all populations. Genetic associations for the CHD phenotypes were evaluated in a linear mixed model using 62,089 SNPs. RESULTS: Multiple SNPs with genome-wide significant and suggestive associations were detected in single-population GWAS and the meta-analysis. Few of these SNPs overlapped between populations or between single-population GWAS and the meta-analysis, suggesting that many CHD-related QTL are population-specific. More significant or suggestive SNPs were identified when FCI grades were used as phenotypes in comparison to the case-control approach. MED13 (Chr 9) and PLEKHA7 (Chr 21) emerged as novel positional candidate genes associated with hip dysplasia. CONCLUSIONS: Our findings confirm the complex genetic nature of hip dysplasia in dogs, with multiple loci associated with the trait, most of which are population-specific. Routinely assessed CHD information collected across countries provide an opportunity to increase sample sizes and statistical power for association studies. While the lack of standardisation of CHD assessment schemes across countries poses a challenge, we showed that conversion of traits can be utilised to overcome this obstacle.

Validation of DNA test for hip dysplasia failed in Danish Labrador Retrievers.

Canine hip dysplasia is characterized by poor hip joint conformation and laxity. The disease is a complex trait influenced by both genetics and environment. Diagnosis and quantification of hip dysplasia are performed by radiographic examination of the hip joint and the diagnosis is used for making breeding decisions in many breeds. A prognostic genetic test (the Dysgen test) based on seven associated SNPs has been developed in a study based on Spanish Labrador Retrievers. In our study this test has been evaluated in 39 Danish Labrador Retrievers with known radiographic hip score: 14 with hip dysplasia (grade D or E) and 25 without hip dysplasia (grade A or B). There was no significant correlation between the Dysgen test results and the radiographic hip status (P = 0.3203) in these dogs, indicating that Dysgen test results obtained for Danish Labrador Retrievers have no prognostic value.

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

BACKGROUND: Hip 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. RESULTS: Using 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. CONCLUSIONS: Our 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.

A veterinary perspective on preventing injuries and other problems that shorten the life of working dogs.

Domesticated dogs are widely used for farm work, law enforcement, military service and in assistance roles. Farm dogs assist farmers by guarding or moving stock, reducing the requirement for human workers and enabling steep terrain to be productive. Working and service dogs are subject to illness and injury, depending on their breed characteristics, activities and the environment in which they work. There are limited data in the veterinary literature on the causes of loss and early retirement of working dogs, and targeted research is required to better determine factors that affect their incidence. Many breeds of working dog suffer from inherited forms of musculoskeletal disease; most importantly, elbow and hip dysplasia. The effectiveness of traditional radiographic (phenotypic) scoring schemes at reducing the prevalence of hip and elbow dysplasia has been variable. The selection of breeding stock should preferably be based on estimated breeding values, rather than on an individual phenotypic score/grade. Nutrition can affect physical and mental performance, disease risk and susceptibility, and recovery from injury, age-associated decline and longevity. The dietary proportions of fat, protein and carbohydrate influence fuel selection during exercise. A common concern among farmers is the difficulty of maintaining body condition in their dogs during periods of heavy work with current feeding practices. Additionally, maintaining a positive calcium balance is necessary for adaptive remodelling in response to exercise. Research strategies should include improved treatment options, the development of more specific means of genetic selection for inherited diseases, investigation into specific nutritional requirements and the dissemination of this knowledge.

Les chiens domestiqués sont très largement utilisés pour travailler dans les fermes, ainsi qu'en tant que chiens policiers, chiens militaires ou chiens d'assistance. Les chiens de ferme aident les éleveurs à garder ou à déplacer leurs troupeaux, ce qui réduit les besoins en main d'oeuvre et permet d'exploiter des terrains escarpés. Les chiens de travail et aidants sont plus ou moins exposés à la maladie et aux blessures, en fonction des caractéristiques de leur race, des tâches qui leur sont confiées et de l'environnement dans lequel ils travaillent. Il n'existe pas beaucoup d'études vétérinaires publiées sur les causes des morts et des mises à la retraite prématurées des chiens de travail, thème qu'il conviendrait d'explorer plus précisément afin de mieux déterminer les facteurs affectant l'incidence de ces problèmes. Plusieurs races canines sont atteintes de troubles musculo-squelettiques héréditaires, dont le plus important est la dysplasie du coude et de la hanche. Les méthodes traditionnelles d'interprétation radiologique (mesure des phénotypes) ont contribué à réduire la prévalence de la dysplasie du coude et de la hanche, avec des résultats variables. La sélection des reproducteurs devrait reposer sur l'estimation de leur potentiel génétique (valeur d'élevage) plutôt que sur le score ou l'échelle de mesure du phénotype d'un individu. L'alimentation joue un rôle sur les performances physiques et mentales, la sensibilité aux maladies et le risque sanitaire, les capacités de rétablissement après une blessure, le processus de vieillissement et la longévité. La proportion relative des lipides, protéines et glucides dans l'alimentation donnée aux chiens détermine les sources d'énergie utilisées durant l'effort. Une préoccupation courante parmi les éleveurs concerne la difficulté de maintenir leurs chiens en bonne condition physique pendant les périodes où le travail est le plus dur, compte tenu des pratiques d'alimentation actuelles. Il est également important de maintenir un bon équilibre en calcium afin de soutenir les capacités d'adaptation à l'effort et de récupération. Les stratégies de recherche devraient explorer les pistes d'amélioration des traitements, mettre au point des méthodes de sélection génétique axées spécifiquement sur les maladies héréditaires et mieux élucider les besoins nutritionnels des chiens, sans oublier de diffuser par la suite les connaissances ainsi obtenues.

El uso del perro doméstico en tareas agrícolas, policiales, militares y de socorro o ayuda está muy extendido. Los perros pastores ayudan al granjero vigilando o conduciendo el ganado, lo que reduce la necesidad de personal humano y permite aprovechar las tierras situadas en terrenos escarpados. Los perros de trabajo y de servicio están sujetos a enfermedades y lesiones que dependen de las características de la raza, la actividad de que se trate y el medio en que esta discurra. En la bibliografía veterinaria hay escasa información sobre las causas que subyacen a la pérdida o la jubilación anticipada de perros de trabajo. De ahí la necesidad de investigar específicamente este aspecto para determinar con más precisión los factores que influyen en ello. Muchas razas de perros de trabajo padecen formas hereditarias de enfermedad musculoesquelética, la más importante de ellas la displasia de codo o cadera. Los tradicionales sistemas de puntuación radiológica (fenotípica) han resultado de eficacia variable para reducir la prevalencia de estas dos displasias. La selección de ejemplares reproductores debería basarse no tanto en la puntuación o grado fenotípico de cada individuo como en los valores estimados de cría. La alimentación puede influir en el rendimiento físico y mental, el riesgo de enfermedades y la sensibilidad a ellas, la recuperación tras una lesión y la longevidad o la decadencia ligada a la edad. Las proporciones de grasas, proteínas y carbohidratos presentes en el régimen alimentario influyen en la selección de combustible metabólico durante la actividad física. Uno de los aspectos que preocupa a todos los granjeros es la dificultad de mantener el cuerpo del perro en condiciones en los periodos de mucho trabajo con las actuales prácticas de alimentación. Además, también es necesario mantener un saldo positivo de calcio para que tenga lugar la remodelación adaptativa del cuerpo en respuesta al ejercicio físico. Los planes de investigación deben incluir aspectos como la búsqueda de mejores alternativas de tratamiento, la obtención de medios más específicos de selección genética respecto de las enfermedades hereditarias, el estudio de necesidades nutricionales específicas y la difusión de cuanto conocimiento resulte de estas investigaciones.

Preventing skeletal and neurological problems in guide dogs for the blind and other working dogs.

Skeletal and neurological problems consistently rank among the top health conditions necessitating the withdrawal or retirement of guide dogs and other working dogs from their service roles. Management practices such as weight management and physical conditioning may help to reduce the incidence of such conditions. However, where there is at least partial genetic aetiology, selective breeding strategies are the only way to produce a lasting reduction in their incidence in future generations. The management of single gene disorders is relatively simple through the judicious use of DNA test results. Breeding strategies to tackle complex diseases, into which category many skeletal and neurological diseases fall, are more challenging but can be successful through the use of data collected through screening schemes and, most efficiently, through the use of estimated breeding values.

Les troubles squelettiques et neurologiques comptent parmi les principaux problèmes de santé imposant la réforme ou la mise à la retraite des chiens guide d'aveugles et autres chiens de travail. Certaines pratiques de bonne gestion veillant notamment à contrôler le poids et la condition physique des chiens peuvent contribuer à réduire l'incidence de ce type de problèmes. Toutefois, lorsque l'étiologie des problèmes de santé est totalement ou partiellement déterminée par la génétique, les stratégies de sélection constituent le seul moyen de réduire durablement cette incidence pour les générations futures. La gestion de certains troubles dus à un gène unique est relativement aisée, grâce à un emploi judicieux des résultats de tests ADN. Lorsqu'il s'agit de maladies plus complexes, catégorie recouvrant nombre d'infections squelettiques et neurologiques, les stratégies de sélection sont plus difficiles à mettre en oeuvre mais elles peuvent réussir si l'on procède à une collecte de données via des dispositifs de dépistage, ou en recourant aux valeurs d'élevage estimées, qui déterminent encore plus efficacement le potentiel génétique d'un chien.

Los problemas esqueléticos y neurológicos se sitúan sistemáticamente entre las principales dolencias que hacen necesario retirar o jubilar a los perros lazarillos y otros perros de trabajo de las tareas que cumplen al servicio del ser humano. Hay procedimientos de gestión, como la regulación del peso o el condicionamiento físico, que pueden ayudar a reducir la incidencia de este tipo de trastornos. Sin embargo, en los casos en que hay, cuando menos parcialmente, una etiología genética, las estrategias de cría selectiva son el único modo de conseguir una reducción duradera de su incidencia en las generaciones futuras. La gestión de trastornos ligados a un solo gen es relativamente sencilla, pues pasa por un uso juicioso de los resultados de las pruebas de ADN. Las estrategias de cría selectiva para combatir enfermedades complejas, categoría en la que entran muchas enfermedades esqueléticas y neurológicas, plantean mayor dificultad, pero pueden deparar buenos resultados cuando se utilizan datos obtenidos con programas de cribado sistemático y ser de lo más eficaces cuando se aplican empleando valores estimados de cría.

Heritabilities and genetic trends for elbow score as recorded by the New Zealand Veterinary Association Elbow Dysplasia Scheme (1992-2013) in four breeds of dog.

AIM: To estimate the heritability of the New Zealand Veterinary Association (NZVA) elbow phenotype, obtain estimated breeding values (EBV) for the worst-elbow score and estimate the genetic trends for this trait in four populous breeds of dogs, using the records from the NZVA Canine Elbow Dysplasia Scheme database (1992-2013). METHODS: Overall, 4,070 elbow records from a pedigree of 11,311 dogs were available for animals scored between 1992 and 2013. The worst elbow score between the left and right elbows was identified for each dog and used for EBV analysis. Estimates of heritability and EBV for the elbow score of dogs from German Shepherd dog, Labrador Retriever, Golden Retriever and Rottweiler breeds were obtained using restricted maximum likelihood procedures with a within-breed linear animal model. The model included the fixed effects of sex and birth year, with age at scoring as a covariable, and the random effect of animal. Genetic trends for the worst-elbow score were calculated as the regression coefficient of the EBV, weighted by reliabilities, on year of birth. RESULTS: The estimates of heritability for worst-elbow score were 0.25 (SE 0.06) in German Shepherd dogs, 0.46 (SE 0.06) in Labrador Retrievers, 0.18 (SE 0.07) in Golden Retrievers and 0.29 (SE 0.11) in Rottweilers. The genetic trend for German Shepherd dogs was -0.0082 (SE 0.0015), for Labrador Retrievers was -0.0016 (SE 0.0016), for Golden Retrievers was -0.0033 (SE 0.0010) and for Rottweilers was -0.0070 (SE 0.0023) units per annum, which were different from zero (p<0.01) in all breeds except Labrador Retrievers. CONCLUSIONS AND CLINICAL RELEVANCE: A small but favourable response to selection was achieved by three of the four breeds in the study period; during which selection for elbow traits has been largely voluntary. While the magnitude of genetic change in terms of elbow units per annum may appear small, it must be remembered that elbow scoring grades only range from 0-3. Greater improvement may be possible if compulsory screening was a requirement for pedigree breeding stock, and if greater selection pressure were applied on the basis on an individual's EBV, rather than the worst-elbow score alone. The maintenance of an open registry, with transparency of EBV information made available to all breeders, may enhance selection intensity opportunities and potentially assist with the process and progress of breeding selection.

Provisional heritability estimates of four distraction index traits in a breeding population of German Shepherd dogs.

AIM To obtain provisional estimates of the heritability (h2 ) of passive laxity of the coxofemoral joints of a breeding colony of German Shepherd dogs, measured using the PennHIP distraction index (DI). METHODS Records were obtained of the PennHIP DI of right and left hips of 195 German Shepherd dogs (377 DI records) from the dog breeding colony of the New Zealand Police Dog Breeding Centre between 2003 and 2016, as well as pedigree records of 884 animals over four generations. Estimates of h2 and variance components for the log transformed DI data were obtained using restricted maximum likelihood procedures with a single trait sire model. Four DI traits for each dog were analysed: left hip, right hip, mean and worse-hip DI. The model included the fixed effects of sex and year of birth, with the age at scoring as a covariable, the random sire effect and residual error for each observation. RESULTS The h2 of the DI of the left hip (0.81, SE 0.40) was higher than the h2 of the DI of the right hip (0.35, SE 0.36). The h2 for the worse-hip DI (0.15, SE 0.28) in each dog was lower than the h2 of the individual hip DI, or the h2 for the mean of the two hips (0.53, SE 0.36) in each dog. The low number of generations prevented a meaningful analysis of the genetic trend. CONCLUSIONS AND CLINICAL RELEVANCE The h2 estimates for the left, right and mean DI traits were moderate to high, whereas the h2 estimates for the worse-hip DI (as used by the PennHIP programme for ranking of dogs) was low, but all estimates had large SE due to the small sample size. This provisional estimate of the h2 of four distraction index traits suggests that the mean DI could be useful as a selection tool against canine hip dysplasia in German Shepherd dogs, whereas the worse-hip DI may be less effective. Heritability estimates from a population with a greater number of DI measures is needed to validate this finding given the large SE in our study.

Quantitative trait loci mapping for canine hip dysplasia and its related traits in UK Labrador Retrievers.

BACKGROUND: Canine hip dysplasia (CHD) is characterised by a malformation of the hip joint, leading to osteoarthritis and lameness. Current breeding schemes against CHD have resulted in measurable but moderate responses. The application of marker-assisted selection, incorporating specific markers associated with the disease, or genomic selection, incorporating genome-wide markers, has the potential to dramatically improve results of breeding schemes. Our aims were to identify regions associated with hip dysplasia or its related traits using genome and chromosome-wide analysis, study the linkage disequilibrium (LD) in these regions and provide plausible gene candidates. This study is focused on the UK Labrador Retriever population, which has a high prevalence of the disease and participates in a recording program led by the British Veterinary Association (BVA) and The Kennel Club (KC). RESULTS: Two genome-wide and several chromosome-wide QTLs affecting CHD and its related traits were identified, indicating regions related to hip dysplasia. CONCLUSION: Consistent with previous studies, the genetic architecture of CHD appears to be based on many genes with small or moderate effect, suggesting that genomic selection rather than marker-assisted selection may be an appropriate strategy for reducing this disease.

Multiple loci associated with canine hip dysplasia (CHD) in German shepherd dogs.

Canine hip dysplasia (CHD) is the most common hereditary skeletal disorder in dogs. To identify common alleles associated with CHD, we developed 37 informative single nucleotide polymorphisms (SNPs) within 13 quantitative trait loci (QTL) previously identified for German shepherd dogs. These SNPs were genotyped in 95 German shepherd dogs affected by CHD and 95 breed, sex, and birth year-matched controls. A total of ten SNPs significant at a nominal P value of 0.05 were validated in 843 German shepherd dogs including 277 unaffected dogs and 566 CHD-affected dogs. Cases and controls were sampled from the whole German shepherd dog population in Germany in such a way that mean coancestry coefficients were below 0.1 % within cases and controls as well as among cases and controls. We identified nine SNPs significantly associated with CHD within five QTL on dog chromosomes (CFA) 3, 9, 26, 33, and 34. Genotype effects of these nine SNPs explained between 22 and 34 % of the phenotypic variance of hip dysplasia in German shepherd dogs. The strongest associated SNPs were located on CFA33 and 34 within the candidate genes PNCP, TRIO, and SLC6A3. Thus, the present study validated positional candidate genes within five QTL for CHD.

Assessing the impact of genomic selection against hip dysplasia in the Labrador Retriever dog.

Many purebred dogs exhibit a higher prevalence of inherited diseases compared with non-purebred dogs. One of the most popular breeds in the UK is the Labrador Retriever, which has a high prevalence of hip dysplasia resulting in high costs for surgical operations and impaired animal welfare. Considering the many complications of highly managed populations, mainly due to breeder's conventions and the resulting population structure, is of great importance for the proper development of a strategy against the disease. In this study, we have compared the utilities and performances of both genomic and phenotypic selection against hip dysplasia in a simulated population with the characteristics of the British Veterinary Association and Kennel Club (BV /KC) hip dysplasia scheme. The results confirm the potential benefits of genomic selection by showing a moderate increase of 1.15-fold (assuming a realistic accuracy of r(2) = 0.5) in response to selection due to the higher accuracy (between 0.96- and 1.32-fold, considering 0.35 ≤ r(2) ≤ 0.7) and more than a threefold increase when all the offspring in each litter are tested (between 3.25- and 4.55-fold, again considering 0.35 ≤ r(2) ≤ 0.7).

Genome wide association study in Swedish Labrador retrievers identifies genetic loci associated with hip dysplasia and body weight.

Genome wide association studies (GWAS) have been utilized to identify genetic risk loci associated with both simple and complex inherited disorders. Here, we performed a GWAS in Labrador retrievers to identify genetic loci associated with hip dysplasia and body weight. Hip dysplasia scores were available for 209 genotyped dogs. We identified a significantly associated locus for hip dysplasia on chromosome 24, with three equally associated SNPs (p = 4.3 × 10-7) in complete linkage disequilibrium located within NDRG3, a gene which in humans has been shown to be differentially expressed in osteoarthritic joint cartilage. Body weight, available for 85 female dogs, was used as phenotype for a second analysis. We identified two significantly associated loci on chromosome 10 (p = 4.5 × 10-7) and chromosome 31 (p = 2.5 × 10-6). The most associated SNPs within these loci were located within the introns of the PRKCE and CADM2 genes, respectively. PRKCE has been shown to play a role in regulation of adipogenesis whilst CADM2 has been associated with body weight in multiple human GWAS. In summary, we identified credible candidate loci explaining part of the genetic inheritance for hip dysplasia and body weight in Labrador retrievers with strong candidate genes in each locus previously implicated in the phenotypes investigated.

Lumbosacral transitional vertebra in 14 dog breeds in Norway: Occurrence, risk factors and association with hip dysplasia.

A lumbosacral transitional vertebra (LTV) is a congenital anomaly of the spine and has been suggested to predispose to canine hip dysplasia (CHD). This retrospective, cross-sectional study investigated the prevalence of LTV and CHD among 14 dog breeds in Norway, the possible associations with risk factors, and whether LTV was a risk factor for the development of hip dysplasia. The results were based on evaluation of ventrodorsal radiographs from the CHD screening program from the Norwegian Kennel Club from February 2014 to January 2022. A total of 13,950 dogs were included in the study. For statistical analysis, CHD grades were reclassified from the official Federation Cynologique Internationale (FCI) grades into three grades: CHD free (CHD=A, B), CHD mild (CHD=C), and CHD severe (CHD=D, E). In the study sample, the overall occurrence of LTV was 18.5%, of which 32.9% were type 1, 45.7% type 2% and 21.4% type 3. The occurrence of LTV varied significantly among the included breeds, ranging from 9.5% to 46.2%. There was no association between sex and LTV. The frequencies of CHD grades were A: 43.1%; B: 31.4%; C: 18.4%; D: 6.0%; E: 1.1%. There was a statistically significant association with mild and severe CHD in dogs with LTV type 2 and LTV type 3 (P< 0.001). In the population studied, the prevalence of LTV was different among breeds. This supports initial data on the heredity of LTV and the diverse occurrence of LTV among breeds. Our results indicate that LTV type 2 and type 3 are associated with mild and severe CHD development. Therefore, this study has potentially identified an additional risk factor for the development of hip dysplasia.

Efficient selection against categorically scored hip dysplasia in dogs is possible using best linear unbiased prediction and optimum contribution selection: a simulation study.

Breeding to reduce the prevalence of categorically scored hip dysplasia (HD), based on phenotypic assessment of radiographic hip status, has had limited success. The aim of this study was to evaluate two selection strategies for improved hip status: truncation selection based on phenotypic record versus best linear unbiased prediction (BLUP), using stochastic simulation and selection scenarios resembling those in real dog populations. In addition, optimum contribution selection (OCS) was evaluated. Two traits were considered: HD (as a categorical trait with five classes and a heritability of 0.45 on the liability scale) and a continuous trait (with a heritability of 0.25) intended to represent other characteristics in the breeding goal. A population structure mimicking that in real dog populations was modelled. The categorical nature of HD caused a considerably lower genetic gain compared to simulating HD as a continuous trait. Genetic gain was larger for BLUP selection than for phenotypic selection in all scenarios. However, BLUP selection resulted in higher rates of inbreeding. By applying OCS, the rate of inbreeding was lowered to about the same level as phenotypic selection but with increased genetic improvement. For efficient selection against HD, use of BLUP breeding values should be prioritized. In small populations, BLUP should be used together with OCS or similar strategy to maintain genetic variation.

Common Orthopedic Traits and Screening for Breeding Programs.

Orthopedic diseases are complex traits, meaning genetics and environmental factors affect risk, making identification of genetic associations difficult. In the United States, hip and elbow scores, patellar luxation scores, Legg-Calvé-Perthes disease, and shoulder osteochondrosis affectedness are available in the Orthopedic Foundation for Animals registry. Distraction indices and extended, ventrodorsal hip conformation scores are recorded by PennHIP. Application of estimated breeding values for hip and elbow dysplasia in breeder selection reduces the severity and prevalence of these traits. Genomic prediction and whole-genome sequence technologies and methods should improve knowledge of genetics underlying orthopedic diseases, leading to improved canine orthopedic genetic quality.

Preliminary transcriptomic analysis of peripheral blood from German Shepherd dogs with degenerative joint disease for the identification of diagnostic biomarkers.

OBJECTIVE: Degenerative joint disease (DJD) includes a group of disorders characterised by the deterioration of the articular cartilage. In this study, we investigated the transcriptomic profile of peripheral blood in German Shepherd dogs with DJD to identify putative diagnostic biomarkers. METHODS: Differential gene expression (DGE) and gene ontology (GO) analyses of the bulk RNA-seq experiment were performed in a cohort of 12 adult dogs (five cases and seven controls, classified by clinical and radiographic analyses). RESULTS: Radiographs of cases revealed severe signs of progressive DJD. Two up-regulated (LOC106559672 and THBS4) and one down-regulated (LOC106559235) differentially expressed genes (adjusted p value < 0.05) were identified. The DGE with log2 fold change < -1.5 and > 1.5 and non-adjusted p < 0.01 were selected for GO analysis. No significant enrichment terms were observed in the selected threshold. CONCLUSION: The gene-encoding protein THBS4 is correlated with DJD severity and long noncoding RNA LOC106559235 is probably involved in the DJD process. The THBS4 gene should be considered a good biomarker for DJD in dogs. Future studies using independent cohorts will be necessary to validate the present results.

Estimation of genetic parameters for hip dysplasia in Czech Labrador Retrievers.

The objective of this study was to estimate the genetic parameters, genetic trends and breeding values using linear model (LM) and threshold model (TM) for the development of hip dysplasia (HD) in Labrador Retrievers in the Czech Republic (n = 3151). The right and left hip joints were evaluated separately using the Fédération Cynologique Internationale scoring system. Four linear and four TMs were tested for the correct estimation of genetic parameters. All the tested models utilized fixed effects of sex, assessor, year of birth, regression of age at evaluation, random direct genetic effects and the effect of the animals' permanent environments. The models differed in the inclusion of the following effects: fixed effects of regression of inbreeding coefficient, random maternal effect and random effect of the maternal permanent environment. Compared to the TM, the LM provided lower coefficients of direct (0.25-0.29 versus 0.26-0.35) and maternal heritability (0.01-0.02 versus 0.03-0.05), repeatability (0.76-0.77 versus 0.78-0.83) and of the correlation between direct and maternal effects (-0.55 to -0.21 versus -0.80 to -0.27). In the tested models, no statistical significance was found for fixed regression of inbreeding coefficients or for the random effect of the permanent maternal environment. In spite of the similarity of the LM and TM results, the TM is recommended as the more suitable model for estimating genetic parameters and subsequent breeding values for HD in Labrador Retrievers in the Czech Republic.

Prime editor-mediated correction of a pathogenic mutation in purebred dogs.

Canine hip dysplasia (HD) is a multifactorial disease caused by interactions between genetic and environmental factors. HD, which mainly occurs in medium- to large-sized dogs, is a disease that causes severe pain and requires surgical intervention. However, the procedure is not straight-forward, and the only way to ameliorate the situation is to exclude individual dogs with HD from breeding programs. Recently, prime editing (PE), a novel genome editing tool based on the CRISPR-Cas9 system, has been developed and validated in plants and mice. In this study, we successfully corrected a mutation related to HD in Labrador retriever dogs for the first time. We collected cells from a dog diagnosed with HD, corrected the mutation using PE, and generated mutation-corrected dogs by somatic cell nuclear transfer. The results indicate that PE technology can potentially be used as a platform to correct genetic defects in dogs.

Canine hip dysplasia is predictable by genotyping.

OBJECTIVE: To establish a predictive method using whole genome genotyping for early intervention in canine hip dysplasia (CHD) risk management, for the prevention of the progression of secondary osteoarthritis (OA), and for selective breeding. DESIGN: Two sets of dogs (six breeds) were genotyped with dense SNPs covering the entire canine genome. The first set contained 359 dogs upon which a predictive formula for genomic breeding value (GBV) was derived by using their estimated breeding value (EBV) of the Norberg angle (a measure of CHD) and their genotypes. To investigate how well the formula would work for an individual dog with genotype only (without using EBV), a cross validation was performed by masking the EBV of one dog at a time. The genomic data and the EBV of the remaining dogs were used to predict the GBV for the single dog that was left out. The second set of dogs included 38 new Labrador retriever dogs, which had no pedigree relationship to the dogs in the first set. RESULTS: The cross validation showed a strong correlation (R>0.7) between the EBV and the GBV. The independent validation showed a moderate correlation (R=0.5) between GBV for the Norberg angle and the observed Norberg angle (no EBV was available for the new 38 dogs). Sensitivity, specificity, positive and negative predictive values of the genomic data were all above 70%. CONCLUSIONS: Prediction of CHD from genomic data is feasible, and can be applied for risk management of CHD and early selection for genetic improvement to reduce the prevalence of CHD in breeding programs. The prediction can be implemented before maturity, at which age current radiographic screening programs are traditionally applied, and as soon as DNA is available.