WP4 Neurological disorders

WP4.1 Behaviour – Leader : Norwegian School of Veterinary Medicine

Around 25% of Americans suffer from a diagnosable mental disorder in a given year. Mental illness, including suicide, accounts for over 15 percent of the burden of disease in established market economies, which is more than the disease burden caused by all cancers. There is strong evidence for an inherited component in the determinism of the most severe mental disorders but the genetic architecture is extremely complex and the identification of susceptibility loci that might yield novel targets for drug development has proven very difficult in the human. Several of the important psychiatric diseases, like bipolar disorder, schizophrenia, obsessive compulsive disorder, borderline personality disorder, alcohol abuse and ADHD, have a component of aggression and/or anxiety in the diagnosis, suggesting that important pathways involved in one or more of these diseases could be identified in this study.

Aggressive behaviour : “Cocker Rage”

It is well established that many dog breeds exhibit specific behaviours often manifest in their denomination (e.g. retrievers, pointers, terriers or shepherds) and resulting from conscious selection decision towards specific utilities. However, aggression is one of the non-selected behaviours that show marked breed-specificity. Surprisingly, specific lines of English Cocker Spaniels (ECS) are well known to exhibit pathological forms of aggressive behaviour. An investigation in Norway, based on questionnaires to veterinarians, indicated at least a 10 time increase in risk for euthanasia due to aggression among Cockers compared to other breeds. A similar disease is also seen in a related breed, the English springer spaniel.

The disorder is characterized by fast changes in mood. In most situations the dogs are friendly, but can periodically show sudden attacks of bad mood or aggression. Aggression is often directed towards the owners, and a high percentage of owners who happen to have a dog with the disorder are bitten by their own dog. Sometimes the aggression is characterised by sudden, un-warned attacks. Relatively soon after these “attacks”, the dog seems ashamed, and returns to a period as a very friendly dog. The breed specificity and familial clustering within breed leaves no doubt about the strong inherited component underlying this trait so the goal of this study is the identification of genetic factors sustaining this type of aggressive behaviour.

WP4.2 Epilepsy – Leader : University of Helsinki

Epilepsy afflicts at least 1% of humans worldwide and consists of a heterogeneous array of neurological disorders with unique clinical presentations and different underlying causes and natural histories. Forty percent of epilepsy is genetically determined. Current epilepsy treatments remain symptomatic and one third of patients who suffer from intractable seizures do not respond to any pharmacological interventions. Several human epilepsy genes have been identified, but these are for rare syndromes in very rare large families displaying Mendelian inheritance, with most identified genes encoding ion channel subunits. The common human epilepsies have proven extremely difficult to study genetically, as many families that appear to have genetic epilepsy do not exhibit uniform seizure types or Mendelian inheritance. Most individuals with epilepsy have no known affected relatives. This is indicative of a complex multigenic disease which will require large sample sizes (thousands of patients) to attain sufficient statistical power for association studies.

Epilepsy is the most prevalent canine neurological disorder, and has been identified by breeders as one of the top three diseases of concern. Epilepsy is a propensity to have seizures. In the brain, a seizure consists of synchronized firing of large numbers of neurons. There are two main types of seizures: focal-onset and primarily generalized. Seizures can produce brain damage resulting in cognitive decline and more frequent seizures. Between 20-60% of dogs with idiopathic epilepsy die as a direct result of their seizure disorder, leading to a shorter life expectancy. Canine epilepsy is estimated to afflict more than 3% of dogs, in some breeds the incidence is as high as 20 percent. The high prevalence of epilepsy in purebred canine families is indicative of a strong genetic component. The forms of epilepsy that afflict different breeds of dog vary considerably in their characteristic seizure activity, age of onset and mode of inheritance and it is likely that different genes are involved in the development of epilepsy in different breeds.

Canine epilepsy models are unique in representing naturally-occurring spontaneous models of human epilepsy. The aim of the study is the discovery of epilepsy-causing mutations in several different genes. It is likely that orthologs of these genes will contribute to the development of human epilepsy. These new epilepsy genes will increase our understanding of pathways involved in this extremely common neurological disease. Furthermore, the various canine epilepsy families will provide useful animal models for pathological and therapeutic studies.