1425: Identification of Epilepsy-Causing Mutations from the Associated Loci by Next-Generation Resequencing

Grant Status: Closed

Grant Amount: $85,040.1
Hannes T Lohi, PhD; University of Helsinki and the Folkhälsan Institute of Genetics
January 1, 2011 - June 30, 2012

Sponsor(s): American Belgian Tervuren Club, Inc., American Chinese Crested Club, American Spaniel Club Foundation, Australian Shepherd Health & Genetics Institute, Belgian Sheepdog Club of America, Inc., Border Terrier Club of America, Estate of Virginia Lyn Tarquinio, German Shorthaired Pointer Club of America, Golden Retriever Foundation, International Alliance for the Health of the Alaskan Malamute, Irish Water Spaniel Club of America, Irish Wolfhound Club of America, Inc., Japanese Chin Club of America, Miniature Pinscher Club of America, Inc., National Beagle Club, Norwich Terrier Club of America, Penn Ridge Kennel Club, Inc., Poodle Club of America Foundation, Rhodesian Ridgeback Club of the United States, Toby's Foundation

Breed(s): Border Terrier, Belgian Tervuren
Research Program Area: Epilepsy Initiative
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Project Summary

The aim of this study was to use the latest sequencing technologies to capture the mutations in previously identified epilepsy loci in three different breeds, Belgian Shepherds, Kromfohrländers and Border Terriers. We have performed several experiments and resequenced the identified regions in Belgian Shepherd and Border Terrier breeds. We have found thousands of variants in each sample across the regions and are in a process of organizing them according to their types and functionality, e.g. coding variants, SNPs, indels, location at regulatory elements. This analysis is followed by comparison between cases and controls to identify those variants that appear only in the epileptic dogs. The most promising variants are validated in our larger cohorts to confirm their causality. In our preliminary analysis, we found nine coding variants in epileptic Belgian Shepherds but none of them has validated as causative so far. Due to technical issues in the array-based capture experiment, the data quality was lower than expected, and we are performing a new capture and resequencing experiment with more samples and improved technology to make sure we have the best possible data in the analysis. The quality of our Border Terrier sequencing data of eight dogs is high and involves two chromosomal regions. We have found thousands of variants in each sample are in a process of validating the most promising candidate mutations in a larger sample cohort. Meanwhile, we have also genotyped a new cohort of epileptic and control dogs from UK and identified a third candidate locus at CFA24. This locus will be confirmed and further investigated in additional samples. Our plan with Kromfohrländers included replication of the locus at CFA28 before its sequencing for mutation. The breed is small and sample recruiting has been slower and prevented us from the replication experiment with a case-control approach. However, we have samples from dogs closely related with each other, and we performed the first replication attempt by using relatives to the dogs that were included in our initial genome scan, but this approach did not confirm our findings as the association remained modest. We also sequenced a candidate gene previously found in human in the region from affected dogs, but did not identify causative variants. Meanwhile we try to encourage the owners and breeders to participate actively to increase the size of our study cohort. Besides the breeds included in our original application, we have made progress also in two other breeds with idiopathic epilepsy including Schipperke and Norwich Terrier. We have mapped putative loci also in these breeds and have performed similar capture sequencing experiments to identify the mutations. Finally, we have been able to collect hundreds of new cases in many breeds and if any mutations are found all breeds can be screened for them. Overall, we have progressed mostly as expected but need still experiments to identify the actual causative variants in the target breeds.

Publication(s)

Koskinen, L. L. E., Seppälä, E. H., Belanger, J. M., Arumilli, M., Hakosalo, O., Jokinen, P., … Lohi, H. (2015). Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene. BMC Genomics, 16(1). https://doi.org/10.1186/s12864-015-1651-9

Koskinen, L. L. E., Seppälä, E. H., Weissl, J., Jokinen, T. S., Viitmaa, R., Hänninen, R. L., … Lohi, H. (2017). ADAM23 is a common risk gene for canine idiopathic epilepsy. BMC Genetics, 18(1). https://doi.org/10.1186/s12863-017-0478-6

Lequarré, A.-S., Andersson, L., André, C., Fredholm, M., Hitte, C., Leeb, T., … Georges, M. (2011). LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs. The Veterinary Journal, 189(2), 155–159. https://doi.org/10.1016/j.tvjl.2011.06.013

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