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Research Update for Toby's Foundation co-sponsored CHF Grant:
Identification of Genetic Risk Factors for Canine Epilepsy
Dr. Gary Johnson, University of Missouri, Columbia
May 2019
This investigation of canine epilepsy had two objectives: (1) to identify genetic variation that occurs within a single breed and increases the chances for breed members to develop epilepsy; and (2) to identify genetic variation that occurs in many breeds and increases the chances of developing epilepsy for any dog that carries the variation. For objective one, two potential epilepsy risk factors show promise and are the subjects of ongoing investigation.
For the second objective, three potential epilepsy risk factors were identified and should be validated with other collections of DNA samples from epileptic and non-epileptic dogs before used for mate selection.
This is the final report for this grant, please visit tobysfoundation.org to read more about this grant and others. There is some promising news but more research will be needed. This is a complex issue and taking longer than we wanted but we will get there! We need your help so we can continue toward our goal of a screening test for epilepsy!
September 2018
In part 1 of the study, work is just started on an eighth potential breed-specific genetic factor. in addition, we expect to evaluate additional risk factor candidates identified in the last five whole genome sequences.
As soon as the final five whole genome sequences from part 1 become available, we will add them our database of whole genome sequences and begin work on part 2. Initially we proposed to evaluate 15-to-25 candidate risk factors. We expect new alternative technology to enable the evaluation of twice that many epilepsy risk factor candidates.
May 2017
Using a novel whole genome sequencing approach we will identify DNA variations in epileptic dogs that could affect the function of genes such as ion channels and neurotransmitter receptors that have been shown to alter the seizure threshold in humans or rodents. We will then directly compare the frequency of those variations in populations of epileptic and non-epileptic dogs rather than using the indirect markers used in traditional mapping studies. We predict that the increased power provided by looking for specific candidate variations rather than linked markers will permit the identification of epilepsy risk factors. These can then be developed into DNA tests to enable breeders to select against those risk factors.
December 2017
This study has two parts. Part 1 is to first use the DNA from epileptic purebred dogs produce whole genome sequences and to identify potential breed-specific genetic factors that increase the likelihood that a dog will develop epilepsy. We proposed to generate and analyze whole genome sequences from at least 14 epileptic dogs. So far whole genome sequences from 18 epileptic purebred dogs have been generated and analyzed. Samples from three additional epileptic dogs have been submitted to a sequencing center in St. Louis, Missouri and we expect to receive the whole genome sequence data from these three dogs in the next two weeks. Two additional samples are scheduled for shipment to the sequencing center in two weeks. The second step to part 1 is to select high-priority breed-specific genetic factors and use DNA tests to see if they occur more often in epileptic dogs then in non-epileptic dogs of the same breed. We proposed to evaluate at least seven high-priority breed-specific genetic factors. So far we have completed the evaluation of five of them, but none have proven to be genetic risk factors for epilepsy. Preliminary results for a sixth genetic risk factor, this one in English Setters, look promising; however, we will need to test several addition epileptic English Setters to validate our findings. Work is just started on a seventh potential breed-specific genetic factor. We expect to continue evaluating additional risk factors in the next 6 months. The second part of the study is to analyze then whole genome sequences from more than 200 epileptic and non-epileptic dogs to identify any genetic factors that increase the risk for developing epilepsy in multiple breeds. As soon as all of the 23 whole genome sequences from part one become available, we will add them to our database of whole genome sequences and begin work on part 2.
December 2016
Epilepsy is one of the most common neurologic diseases of dogs and a top concern of dog breeders. Despite strong evidence that genetics is important in determining the risk of idiopathic epilepsy, numerous gene mapping studies have failed to identify a locus that accounts for that risk in either dogs or humans. Seizures occur when excessive activity goes beyond the normal threshold for brain function, many factors contribute to that level of activity, and therefore, mutations in numerous genes may collectively contribute to increased activity until that threshold is exceeded, resulting in epilepsy. Any one of these mutations may be present in non-epileptic dogs, but because it only partially alters activity, it would not produce seizures. Therefore, traditional gene mapping studies might overlook that mutation. Using a novel whole genome sequencing approach the investigators hope to identify DNA variations in epileptic dogs that could affect the function of genes such as ion channels and neurotransmitter receptors that have been shown to alter the seizure threshold in humans or rodents. The frequency of such variations in populations of epileptic and non-epileptic dogs will be directly compared rather than the indirect markers used in traditional mapping studies. The increased power provided by looking for specific gene candidate variations rather than linked markers will aid the identification of epilepsy risk factors, perhaps leading to the development of DNA tests to enable breeders to select against such risk factors.