Cataracts in Havanese: genome wide association study reveals two loci associated with posterior polar cataract.

BACKGROUND: Cataract is considered an important health issue in Havanese, and studies indicate a breed predisposition. Possible consequences of cataracts include lens induced uveitis, reduced eyesight, and blindness in severe cases. Reducing the prevalence of cataracts could therefore improve health and welfare significantly. The most frequently diagnosed forms of cataract in Havanese are cortical- and anterior suture line cataract, but cases of posterior polar cataract are also regularly reported. Out of the three, posterior polar- and cortical cataracts are considered the most clinically relevant. RESULTS: We performed a genome wide association study that included 57 controls and 27 + 23 + 7 cases of cortical-, anterior suture line- and posterior polar cataract, respectively. An association analysis using a mixed linear model, revealed two SNPs on CFA20 (BICF2S23632983, p = 7.2e-09) and CFA21 (BICF2G630640490, p = 3.3e-09), that were significantly associated with posterior polar cataract, both of which are linked to relevant candidate genes. The results suggest that the two variants are linked to alleles with large effects on posterior polar cataract formation, possibly in a dominant fashion, and identifies regions that should be subject to further sequencing. Promising regions on CFA4 and CF30 were also identified in the association analysis of cortical cataract. The top SNPs on each chromosome, chr4_12164500 (p = 4.3e-06) and chr30_28836339 (p = 5.6e-06), are located within, or in immediate proximity to, potential cataract candidate genes. The study shows that age at examination is strongly associated with sensitivity of cataract screening. Havanese in Norway are on average 3.4 years old when eye examinations are performed: an age where most dogs that are genetically at risk have not yet developed clinically observable changes. Increasing the average age of breeding animals could increase accuracy of selection, leading to improved health. CONCLUSIONS: The study identified two loci, on CFA20 and CFA21, that were significantly associated with posterior polar cataract in Havanese. SNPs that showed putative association with cortical cataracts, were observed on CFA4 and CFA30. All the top SNPs are located in close proximity to cataract candidate genes. The study also show that sensitivity of cataract screening is highly dependent on age at examination.

A 1 bp deletion in HACE1 causes ataxia in Norwegian elkhound, black.

A number of inherited ataxias is known in humans, with more than 250 loci implicated, most of which are included in human ataxia screening panels. Anecdotally, cases of ataxia in the Norwegian elkhound black have been known for the last 40 years. Affected puppies from three litters were clinically and neurologically examined, and postmortem samples were collected for morphological studies, including ultrastructural analyses. The puppies displayed vestibulocerebellar neurological signs and had degenerative histopathological alterations in cerebellum and brain stem. Three affected dogs, each from different litters, as well as both parents and one healthy littermate from each litter, were whole genome sequenced. Through variant calling we discovered a disease-associated 1 bp deletion in HACE1 (CFA12), resulting in a frameshift at codon 333 and a premature stop codon at codon 366. The perfect association combined with the predicted significant molecular effect, strongly suggest that we have found the causative mutation for Norwegian elkhound black ataxia. We have identified a novel candidate gene for ataxia where dogs can serve as a spontaneous model for improved understanding of ataxia, also in human.

Heritability of distichiasis in Havanese dogs in Norway.

BACKGROUND: Distichiasis is a presumed inherited eyelid disease, characterized by misplaced eyelashes. The effect on eye health and animal welfare varies between individuals; most mild cases show no clinical signs, but some affected animals develop painful corneal disease. In this study, we investigated the prevalence and heritability of distichiasis in the Norwegian population of Havanese dogs. RESULTS: A total of 1156 Havanese were included in the study. Out of these, 168 were affected with distichiasis, making the prevalence in our sample 14.5% (95% CI 12.5-16.6%). There was no sex predisposition. Most affected individuals were graded "mildly affected". The estimates generally showed high heritabilities, which varied between 0.276 (linear model) and 0.720 (Bayesian threshold model). The linear estimates, after conversion to the underlying scale (h2l = 0.664-0.674), corresponds well to the results of the Bayesian models. CONCLUSIONS: The estimated heritability of distichiasis in Havanese is high and the prevalence is moderate. The high heritability indicate that a significant selection response could be obtained by simple mass selection. To secure good animal welfare, it's important to control the number of affected individuals and especially the severely affected.

Distichiasis is an eye condition, characterized by misplaced eyelashes, that is frequently seen in dogs. Some dog breeds appear to be more at risk than others. The degree of clinical signs in affected dogs varies a lot. Many mild cases appear to be completely asymptomatic, while others suffer pain and damage to the eye, which necessitates removal of the hairs.In this study, we investigate both how common distichiasis is in the Havanese dog breed and estimate the degree of genetic influence on the trait. We find that 14.5% of eye screened Havanese, registered in the Norwegian Kennel Club, are affected with distichiasis. Most cases are graded "mild". There is no significant difference in how many males and females are affected.We find high heritability estimates of distichiasis in Havanese (≈0.28 calculated by linear models and 0.59-0.72 calculated by Bayesian threshold models), showing a high genetic influence on the trait. The high estimated heritability mean that it should be possible to reduce the prevalence of the condition, and contribute to improved animal welfare, though systematic breeding.We recommend that all Havanese are eye screened prior to breeding, to control the prevalence of distichiasis, as well as other eye conditions that are relevant in the breed, like cataracts. Dogs with severe distichiasis or ectopic cilia should not be bred. Dogs with mild or moderate distichiasis may be bred to an unaffected partner.

Short and sweet: foreleg abnormalities in Havanese and the role of the FGF4 retrogene.

BACKGROUND: Cases of foreleg deformities, characterized by varying degrees of shortened and bowed forelegs, have been reported in the Havanese breed. Because the health and welfare implications are severe in some of the affected dogs, further efforts should be made to investigate the genetic background of the trait. A FGF4-retrogene on CFA18 is known to cause chondrodystrophy in dogs. In most breeds, either the wild type allele or the mutant allele is fixed. However, the large degree of genetic diversity reported in Havanese, could entail that both the wild type and the mutant allele segregate in this breed. We hypothesize that the shortened and bowed forelegs seen in some Havanese could be a consequence of FGF4RG-associated chondrodystrophy. Here we study the population prevalence of the wild type and mutant allele, as well as effect on phenotype. We also investigate how the prevalence of the allele associated with chondrodystrophy have changed over time. We hypothesize that recent selection, may have led to a gradual decline in the population frequency of the lower-risk, wild type allele. RESULTS: We studied the FGF4-retrogene on CFA18 in 355 Havanese and found variation in the presence/absence of the retrogene. The prevalence of the non-chondrodystrophic wild type is low, with allele frequencies of 0.025 and 0.975 for the wild type and mutant allele, respectively (linked marker). We found that carriers of the beneficial wild type allele were significantly taller at the shoulder than mutant allele homozygotes, with average heights of 31.3 cm and 26.4 cm, respectively. We further found that wild type carriers were born on average 4.7 years earlier than mutant allele homozygotes and that there has been a gradual decline in the population frequency of the wild type allele during the past two decades. CONCLUSIONS: Our results indicate that FGF4RG-associated chondrodystrophy may contribute to the shortened forelegs found in some Havanese and that both the wild type and mutant allele segregate in the breed. The population frequency of the wild type allele is low and appear to be decreasing. Efforts should be made to preserve the healthier wild type in the population, increase the prevalence of a more moderate phenotype and possibly reduce the risk of foreleg pathology.