This is the first study to evaluate the heritability of OSA in Irish Wolfhounds. Canine OSA has a poor prognosis, with less than 45% of dogs surviving > 1 year after diagnosis despite treatment [1, 2]. This disease is particularily devastating to the Irish Wolfhound breed, which has been reported to affect between 8 and 20% of the population [4, 5, 19]. OSA is also substantially more common in some breeds than others [19]; diseases that are breed-specific or have substantial breed predisposition have a genetic basis.
The family pedigree and family structure of the dog sample used for this study was also evaluated. The results of this analysis indicated that the pedigree used, consisting of 5110 dogs, was of sufficient size and power to enable an accurate estimation of OSA heritability. It is noteable that 47% of dogs within this population showed some evidence of inbreeding. This is expected, and likely reflective of a study population consisting of a subset of dogs from a pure-bred population. For the Irish Wolfhound breed, this is compounded by the challenge of the breed being less common, narrowing the breeding population further. These challenges are substantial for more unusual or rare breeds of dogs, and are important considerations in investigation of genetic disease as identification of disease associated mutations are important considerations for breed improvement over time. It is also important to note that the inbreeding co-efficients reported in this study relate only to the study population, and cannot be extrapolated to the entire Irish Wolfhound population. Inbreeding leads to loss of diversity at the individual and population levels, which can hinder ability to respond to a changing environment. Having some degree of inbreeding in the closely replated population like in this study is inevitable; inbreeding patterns observed in purebred dogs can be a result from specific breeding practices or founder effects and not be overlay from the current population size [20]. However, the findings in this study are not surprising because smaller populations tend to have proportionally more animals with higher inbreeding coefficients than larger populations.
We estimated the heritability of OSA (h2OSA) in the Irish Wolfhound to be 0.654, indicating that OSA in the Irish Wolfhound breed is a highly heritable complex disease. This heritability estimate indicates that environmental and epigenetic factors also influence disease risk. These results align with an earlier genome wide association study investigating OSA in the Irish Wolfhound, where only four genomic regions were found to associate with disease [9], as well as a meta-analysis study that indicated in individual dogs, Mendelian-level polygenetic risk can be present [10].
We further investigated our study population by evaluating the distribution of parental phenotypes in Irish Wolfhounds assigned as either a case or control. It is noteable that for dogs that developed OSA, a much higher proportion had at least one parent with an OSA diagnosis when compared to the control population. While this data is challenging to interepret due to a large number of case and control dogs for which at least one parental phenotype was not known, it does support the calculated heritability estimate. A reliable risk calculation based on odds of disease development for animals with a known affected parent is not possible with this current dataset due to the large number of affected offspring with at least one parent not having a reported phenotype.
The results presented also mirror findings of OSA in the closely related Scottish Deerhound, where variance component analysis estimated heritability of OSA to be 0.69; in this study, heritability in the Scottish Deerhound was best modeled using a Mendelian major gene model with dominant expression [12]. The findings from Scottish Deerhound OSA are of particular relevance to the Irish Wolfhound due to breed history. In the mid-nineteenth century, Irish Wolfhounds were nearly extinct as a breed. The breed’s revival was due to a combination of identifying dogs suspected to have descended from older Irish Wolfhound strains and cross breeding with Scottish Deerhounds, Great Dane crosses, and a smattering of other dogs including a Borzoi and a Tibetan Mastiff [21]. This breed history is relevant for two reasons: 1) from a genetic standpoint, current Irish Wolfhounds have substantial relatedness to Scottish Deerhounds, and 2) the Irish Wolfhound population descends from a small subset of dogs, resulting in a genetic bottleneck that likely contributes to high rates of disease prevalence [22].
The pattern and heritability seen in this study is substantially different from the OSA inheritance patterns seen in humans, where OSA is a highly complex disease [7]. Disease traits can have many different modes of inheritance. Simple or Mendelian diseases occur when a single genomic mutation is responsible for disease, which can occur with cancers though what is referred to as “cancer predisposition genes” [23]. This is in contrast to highly complex diseases, where multiple genomic variants spread across the genome, in combination with environmental effects, contribute to disease risk. Most cancers follow a complex disease inheritance pattern. Complex diseases vary in the degree to which genetics and environmental effects influence disease risk, and further vary with regards to degrees of polygenicity [14]. Prior literature has informed us that in dogs OSA is a complex disease but the underlying genetic architecture contributing to disease risk is variable between breeds [9]. In breeds such as the Irish Wolfhound and Scottish Deerhound, where heritability estimates are high and literature suggests a finite number of high impact genetic mutations [10, 11], there is a greater likelihood that identification of a few influential OSA mutations can be identified with further research.
Another important difference between human and canine OSA is that in humans OSA is considered a childhood disease, while OSA in most dog breeds is a disease of aged animals. Noteably, the Irish Wolfhound breed is unusual in this regard, having the youngest age of OSA onset of commonly affected breeds [19].
There are a number of limitations to this study. Data was primarly retrieved through an on-line database of Irish Wolfhound pedigrees, and, therefore, diagnosis of OSA was owner reported; medical records were not able to be obtained. Many dogs in the database were noted to be deceased without a cause of death, and it is likely that a number of animals who were affected by OSA were not assigned a phenotype. The decision to define control dogs as those Irish Wolfhounds over 10 years of age was based on a number of factors, including prior literature [19] and data provided by the Irish Wolfhound Foundation (Fig. 3). The Irish Wolfhound, like many giant breeds, has a shorter lifespan [24], with mean lifespan estimates from the past 50 years varing between 6.5 and 8.8 years [25, 26]. Thus 10 years of age is considered very old for this breed. This control age choice was further supported by a lack of any dogs over 10 years of age being reported to have died of OSA during creation of the heritability matrixes used for this study. However, it is possible that some dogs who lived beyond 10 years of age were affected with OSA but were not reported as having such in the Irish Wolfhound database used. It is also possible that dogs who only lived to 10 years of age may have developed OSA had they lived longer. It is difficult to predict how these factors may have influenced results, but the large sample size was purposely created to increase power and decrease the effect of any inaccuracies in phenotyping that may have occurred.