ICCFGG program 2022


#8 Idiopathic epilepsy in the Border Collie: using genome-wide association study and whole genome sequencing approaches to identify genetic risk factors Christopher A. Jenkins1,2 , Luisa De Risio3, Tiina Heinonen4, Jim Johnson1, Lorna J. Kennedy2, Andrea D. Short2, Sofie F. M. Bhatti5, Donna Foster1, Peter Leegwater6, Paul Mandigers6, Tarja Pääkkönen4, Rowena Packer7, Koen Santifort8, Holger Volk9, Cathryn S. Mellersh1, Marjo Hytönen4, Hannes Lohi*4, Sally L. Ricketts*1,2 *Contributed equally cj452@cam.ac.uk 1Kennel Club Genetics Centre, Department of Veterinary Medicine, University of Cambridge, UK; 2Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK; 3Linnaeus Veterinary Ltd, UK; 4University of Helsinki, Finland; 5Ghent University, Faculty of Veterinary Medicine, Belgium; 6University of Utrecht, The Netherlands; 7Royal Veterinary College, UK; 8Evidensia Small Animal Hospital Arnhem, Arnhem, The Netherlands; 9Department of Small Animal Medicine and Surgery, University of Veterinary Medicine, Hannover, Germany Idiopathic epilepsy (IE) is a chronic and life-limiting neurological disorder characterized by recurrent seizures. The Border Collie (BC) is one of the most commonly and severely affected breeds, though little is known regarding the genetic factors that increase this breed’s susceptibility to IE. This large-scale collaborative project aims to identify genetic variants that are consistent- ly associated with IE in the BC. We conducted a genome-wide association study meta-analysis utilizing three study sets genotyped using the Illumina canineHD array – two Kennel Club Genetics Centre (KCGC) sets and one from the University of Helsinki. We define cases as BC diagnosed with IE with at least a tier I level of confidence. Controls are BC over the age of 8 years that have been reported by owners to have never had a seizure. After genotyping a subset of the KCGC sets on the Axiom array, we imputed genotypes to increase the resolution of all three datasets. The analysis included 271 BC (104 cases and 167 controls) and 291,450 SNPs. We identified 20 suggestive as- sociations on 16 canine autosomes using an empirical threshold of association of P <= 1 x 10-4. We subsequently imputed genotypes to whole genome level. This meta-analysis of 123 cases and 187 controls and 5,993,223 SNPs revealed nine additional suggestive association signals at P <= 1 x 10-5. We are validating these 29 SNP associations in an independent replication set of BC com- prising around 200 IE cases and 400 controls. It is likely that IE in the BC is a complex disease, with a polygenic set of risk factors predisposing to greater risk of IE. Improved understanding of the genetic architecture and biological pathways underlying IE in the BC could lead to better treatments and prevention of the disease.


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