Bayesian mixed model analysis uncovered 21 risk loci for chronic kidney disease in boxer dogs.

Chronic kidney disease (CKD) affects 10% of the human population, with only a small fraction genetically defined. CKD is also common in dogs and has been diagnosed in nearly all breeds, but its genetic basis remains unclear. Here, we performed a Bayesian mixed model genome-wide association analysis for canine CKD in a boxer population of 117 canine cases and 137 controls, and identified 21 genetic regions associated with the disease. At the top markers from each CKD region, the cases carried an average of 20.2 risk alleles, significantly higher than controls (15.6 risk alleles). An ANOVA test showed that the 21 CKD regions together explained 57% of CKD phenotypic variation in the population. Based on whole genome sequencing data of 20 boxers, we identified 5,206 variants in LD with the top 50 BayesR markers. Following comparative analysis with human regulatory data, 17 putative regulatory variants were identified and tested with electrophoretic mobility shift assays. In total four variants, three intronic variants from the MAGI2 and GALNT18 genes, and one variant in an intergenic region on chr28, showed alternative binding ability for the risk and protective alleles in kidney cell lines. Many genes from the 21 CKD regions, RELN, MAGI2, FGFR2 and others, have been implicated in human kidney development or disease. The results from this study provide new information that may enlighten the etiology of CKD in both dogs and humans.

Correction: The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels.

[This corrects the article DOI: 10.1371/journal.pgen.1009726.].

The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels.

Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a ~10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs-the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heart-derived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity.

Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs.

BACKGROUND: Hypothyroidism is a common complex endocrinopathy that typically has an autoimmune etiology, and it affects both humans and dogs. Genetic and environmental factors are both known to play important roles in the disease development. In this study, we sought to identify the genetic risk factors potentially involved in the susceptibility to the disease in the high-risk Giant Schnauzer dog breed. RESULTS: By employing genome-wide association followed by fine-mapping (top variant p-value = 5.7 × 10- 6), integrated with whole-genome resequencing and copy number variation analysis, we detected a ~ 8.9 kbp deletion strongly associated (p-value = 0.0001) with protection against development of hypothyroidism. The deletion is located between two predicted Interferon alpha (IFNA) genes and it may eliminate functional elements potentially involved in the transcriptional regulation of these genes. Remarkably, type I IFNs have been extensively associated to human autoimmune hypothyroidism and general autoimmunity. Nonetheless, the extreme genomic complexity of the associated region on CFA11 warrants further long-read sequencing and annotation efforts in order to ascribe functions to the identified deletion and to characterize the canine IFNA gene cluster in more detail. CONCLUSIONS: Our results expand the current knowledge on genetic determinants of canine hypothyroidism by revealing a significant link with the human counterpart disease, potentially translating into better diagnostic tools across species, and may contribute to improved canine breeding strategies.

The genomic signature of dog domestication reveals adaptation to a starch-rich diet.

The domestication of dogs was an important episode in the development of human civilization. The precise timing and location of this event is debated and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencing of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication. Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs.

Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus.

Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10-8). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.

Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs.

BACKGROUND: Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome-wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin-2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities. OBJECTIVES: The main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD-affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location. ANIMALS/METHODS: Skin biopsies were collected from nine CAD-affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology. RESULTS: We observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding-partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed. CONCLUSION: Plakophilin-2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.

Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs.

BACKGROUND: Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. RESULTS: Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10(-7)) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region. CONCLUSIONS: Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.

Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis.

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1 × 10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n cases = 91, n controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0 × 10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 × 10(-7), pgenome = 0.03). The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ~209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds.

BACKGROUND: The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. RESULTS: We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. CONCLUSIONS: We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.

A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 × 10⁻6, p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

Awareness, experiences, and opinions by owners, breeders, show judges, and veterinarians on canine Brachycephalic Obstructive Airway Syndrome (BOAS).

BACKGROUND: Exaggerated brachycephalic features have been highlighted over the last decade by their profound effect on the health and welfare of the affected dogs. The term brachycephalic obstructive airway syndrome (BOAS) was launched in the early 2000s and has received worldwide attention and awareness. At the same time, the popularity of brachycephalic dogs increased. This study aimed to reveal the awareness and experiences of health issues related to the physical appearance of brachycephalic breeds and compare perceptions and opinions on how to counteract these issues by various stakeholders (dog owners, veterinarians, dog breeders, and show judges) by performing an online survey. RESULTS: Altogether, 1602 owners, 1551 breeders, 118 show judges, and 557 veterinarians participated. Awareness and experiences of conformation-related health issues were common among all stakeholder groups. Most participants agreed fully or partly that health issues related to conformity threaten the health of brachycephalic breeds; that the measures taken so far are positive; and that guidelines on the appearance of a dog should be based on knowledge regarding health issues related to physical appearance. A disagreement was noted on further measures to be taken and the importance of adhering to a breed standard. CONCLUSIONS: All stakeholders were aware of health issues related to the appearance of brachycephalic dogs, but had variable personal experiences of these issues. Most participants agreed fully or partly that health issues related to conformity threaten the health of brachycephalic breeds, and that attention to these issues and measures taken so far are positive. However, there is a disagreement on further actions to be taken and the importance of adhering to a breed standard. These findings could be used to understand and bridge the gap in opinions between stakeholders and to refine methods to influence the health of dogs with exaggerated brachycephalic features.

The epidemiology of osteochondrosis in an insured Swedish dog population.

Osteochondrosis (OC) is a focal disturbance of endochondral ossification due to a failure of blood supply to the epiphyseal growth cartilage. In dogs, OC most commonly affects the shoulder joint, followed by the elbow, tarsal, and stifle joints. The condition is associated with clinical signs such as lameness and pain and the prognosis varies depending on the affected joint. Most epidemiologic studies of OC in dogs were performed over 20 years ago, and updated estimates of disease incidence are lacking. Therefore, the objectives of this study were to provide population-based estimates of the incidence rate, cause-specific mortality rate, and age at diagnosis of appendicular OC (AOC, including OC of the shoulder, elbow, stifle, and tarsal joints) and stifle and tarsal OC separately, using data from Agria Djurförsäkring in Sweden (2011-2016). Further, the study aimed to evaluate the risk of OC in subgroups divided by breed and sex and describe previous, concurrent, and subsequent diagnoses of the affected joint in dogs with stifle or tarsal joint OC. The study population included just over 600,000 dogs, of which 685 were affected by AOC. Stifle joint OC (n = 113) was more common than tarsal joint OC (n = 80). The incidence rate of AOC was 3.77 (95% confidence interval (CI): 3.49-4.07) cases per 10,000 dog-years at risk, while the incidence rate of stifle and joint tarsal OC was 0.64 (95% CI: 0.53-0.77) and 0.43 (95% CI: 0.34-0.54) cases per 10,000 dog-years at risk, respectively. All breeds at increased risk of AOC were large or giant, and male dogs had an increased risk of AOC compared to female dogs (RR 1.76, 95% CI: 1.50-2.07, p < 0.001). The median age at first diagnosis during the study period was 0.74 (0.32-11.5) years for AOC, 2.62 (0.45-8.82) years for stifle joint OC, and 0.73 (0.35-7.35) years for tarsal joint OC. Of the dogs with stifle or tarsal joint OC, 30.2% and 15.0% had a previous diagnosis of stifle/tarsal joint pain or other unspecific clinical signs, respectively, and 13.8% of the dogs with stifle joint OC suffered subsequent cruciate ligament rupture. Osteochondrosis was the most common reason for euthanasia in the affected dogs. In total, 77 dogs were euthanised due to AOC during the study period.

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.

Heritability and genetic trend of body weight in dogs of different breeds in Sweden.

High body weight (BW) in dogs has been associated with developmental as well as degenerative diseases, but the heritability of BW in dog breeds is largely unknown. The aim of the current study was to estimate heritability and genetic change (genetic trend) for BW in a range of dog breeds in Sweden. Body weight registrations from 19 dog breeds (with n ranging from 412 to 4,710) of varying body size, type and usage were collected from 2007 to 2016. The average BW of the breeds was 8 to 56 kg. The BW registrations were performed when the dogs were 12 to 24 mo of age (18 to 30 mo for one large-sized breed) in connection with an official radiographic screening program for hip dysplasia. Collected weight records were used to estimate heritability and genetic trends for BW. Several statistical models were used. The preliminary model included the fixed effects of breed (P < 0.001), sex (P < 0.001), year of screening (P < 0.001), litter size (P = 0.06), parity of the dam (P = 0.03) and linear regression on age at screening (P < 0.001), the latter five effects all nested within breed, and the random effects of litter and dam. Season of birth and the quadratic effect of age were also tested, but were not significant (P > 0.10). For the genetic analysis, various mixed linear models were tested within breed with different combinations of random effects; the most complex model included random effects of litter, direct additive, and maternal genetic effects, and maternal permanent environmental effects. The average heritability for BW over all 19 breeds was 51%, with a range of 35% to 70%, and the additive genetic coefficient of variance was around 9%. Maternal heritability was 5% to 9% and litter variance was below 10% with one exception (15% in Shetland Sheepdogs). For nine breeds, there was a genetic trend of increasing BW, whereas seven breeds had a genetic trend of decreasing BW. The largest absolute genetic change over a 10-yr period was around 0.6 kg or about 2% of the mean. In conclusion, given the small genetic changes in spite of the high heritability, it seems that there is generally a very weak selection, if any, for BW in the included dog breeds.

High body weight in dogs is often considered to cause problems, for instance, resulting in hip and elbow diseases. Furthermore, there is a huge variation in body conformation and size between different dog breeds, which is related to breeding for specific appearances and genetic traits. The aim of this study was to investigate the genetic variation of body weight within different dog breeds. To study this, we examined 19 dog breeds with an average body weight of 8 to 56 kg. We found that on average about 50% of the total variation in body weight between dogs, within a breed, depends on genetic differences, but with a range from 35% to 70% depending on breed. There were rather small changes over time in the genetic predisposition for high or low body weight; the largest changes were 0.6 kg over a 10-yr period.

Multiple Genetic Loci Associated with Pug Dog Thoracolumbar Myelopathy.

Pug dogs with thoracolumbar myelopathy (PDM) present with a specific clinical phenotype that includes progressive pelvic limb ataxia and paresis, commonly accompanied by incontinence. Vertebral column malformations and lesions, excessive scar tissue of the meninges, and central nervous system inflammation have been described. PDM has a late onset and affects more male than female dogs. The breed-specific presentation of the disorder suggests that genetic risk factors are involved in the disease development. To perform a genome-wide search for PDM-associated loci, we applied a Bayesian model adapted for mapping complex traits (BayesR) and a cross-population extended haplotype homozygosity test (XP-EHH) in 51 affected and 38 control pugs. Nineteen associated loci (harboring 67 genes in total, including 34 potential candidate genes) and three candidate regions under selection (with four genes within or next to the signal) were identified. The multiple candidate genes identified have implicated functions in bone homeostasis, fibrotic scar tissue, inflammatory responses, or the formation, regulation, and differentiation of cartilage, suggesting the potential relevance of these processes to the pathogenesis of PDM.

Demography and disorders of English Cocker Spaniels under primary veterinary care in the UK.

BACKGROUND: The English Cocker Spaniel (ECS) is a common family dog in the UK. This study aimed to describe demography, morbidity, and mortality in ECS under primary veterinary care in the UK during 2016 using data from the VetCompass™ Programme. This study hypothesised that the prevalence of aggression is higher in male than female ECS, and higher in solid-coloured than bi-coloured ECS. RESULTS: English Cocker Spaniels comprised 10,313/336,865 (3.06%) of dogs under primary veterinary care during 2016. The median age was 4.57 years (inter-quartile range (IQR) 2.25-8.01) and the median adult bodyweight was 15.05 kg (IQR 13.12-17.35). The annual proportional birth rate was relatively stable between 2.97-3.51% from 2005-2016. The most common specific diagnoses were periodontal disease (n = 486, prevalence 20.97%, 95% confidence interval (CI): 19.31-22.62), otitis externa (n = 234, 10.09%, 95% CI: 8.87-11.32), obesity (n = 229, 9.88%, 95% CI: 8.66-11.09), anal sac impaction (n = 187, 8.07%, 95% CI: 6.96-9.18), diarrhoea (n = 113, 4.87%, 95% CI: 4.00-5.75), and aggression (n = 93, 4.01%, 95% CI: 3.21-4.81). The prevalence of aggression was higher in males (4.95%) than in females (2.87%) (P = 0.015) and in solid-coloured (7.00%) than in bi-coloured dogs (3.66%) (P = 0.010). The median age at death was 11.44 years (IQR 9.46-13.47) and the most common grouped causes of death were neoplasia (n = 10, 9.26%, 95% CI: 3.79-14.73), mass-associated disorders (n = 9, 8.33%, 95% CI: 4.45-15.08), and collapse (n = 8, 7.41%, 95% CI: 3.80-13.94). CONCLUSIONS: Periodontal disease, otitis externa, and obesity are identified as the most common health issues for ECS, and neoplasia and mass-associated disorders as the most common reasons for death. The prevalence of aggression was higher in males and solid-coloured dogs. The results can aid veterinarians in giving evidence-based health and breed choice information to dog owners and highlights the importance of thorough oral examination and body condition score evaluation during routine veterinary examination of ECS.

The English Cocker Spaniel (ECS) is a popular family dog in the UK, but there is limited information regarding common disorders affecting the breed. The goal of this study was to describe demography (age, sex, neuter, and bodyweight), disease occurrence, lifespan, and reasons for death in ECS by using data from the VetCompass™ Programme. The VetCompass™ Programme collects information from anonymised clinical records of dogs attending first-opinion veterinary practices in the UK. This study hypothesised that aggression is more common in males than in females, and in solid-coloured than in bi-coloured ECS dogs.English Cocker Spaniels comprised 10,313/336,865 (3.06%) of dogs under primary veterinary care during 2016. Breed popularity did not vary much from 2005 to 2016, comprising around 3% of all dogs born each year. The average age of dogs in 2016 was 4.57 years and the average adult bodyweight was 15.05 kg. The most common disorders were periodontal disease (infection of the tissues that hold the teeth in place, affecting 20.97% of the dogs), inflammation of the external ear canal (10.09%), obesity (9.88%), anal sac impaction (8.07%), diarrhoea (4.87%), and aggression (4.01%). Aggression was more common in males (4.95%) than in females (2.87%) and in solid-coloured (7.00%) than in bi-coloured (3.66%) dogs. The frequency of aggression also varied across the four most common solid colours (black, liver, golden, red), with golden-coloured dogs showing the most aggression (12.08%). The average lifespan was 11.44 years and the most common cause of death was tumours.This study shows that first-opinion clinical records can help us to understand and enhance breed health. The results can guide veterinarians in giving breed-adapted information to owners of ECS and help breeders to optimise breeding decisions. Further, this information can be used by future ECS owners to make more informed decisions when acquiring a dog if avoidance of aggression is a key priority. Periodontal disease was the most common condition affecting the breed, which highlights the importance of regular veterinary dental checks and as well as tooth brushing in ECS.

Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene.

Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNA(Tyr) gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0-11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNA(Tyr) had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNA(Tyr) gene is the causative mutation for SAN.