ADAM23 is a common risk gene for canine idiopathic epilepsy

Abstract

BackgroundIdiopathic or genetic adult-onset epilepsy is a common neurological disorder in domestic dogs. Genetic association has been reported only with ADAM23 on CFA 37 in few breeds. To identify novel epilepsy genes, we performed genome-wide association (GWA) analyses in four new breeds, and investigated the association of the previously reported ADAM23 haplotype with the epilepsy phenotype in eight breeds.ResultsGWA analysis did not reveal new epilepsy loci. ADAM23 association (p < 0.05) was identified in five breeds. Combined analysis of all eight breeds showed significant association (p = 4.6e−6, OR 1.9).ConclusionsOur results further support the role of ADAM23 in multiple breeds as a common risk gene for epilepsy with low penetrance. The lack of findings in the GWA analyses points towards inefficient capture of genetic variation by the current SNP arrays, causal variant(s) with low penetrance and possible phenocopies. Future work will include studies on ADAM23 function and expression in canine neurons, as well as whole-genome sequencing in order to identify additional IE genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-017-0478-6) contains supplementary material, which is available to authorized users.

Risk loci for idiopathic epilepsy in Belgian Shepherd dogs

“…recently reported the identification of loci on canine chromosome 14 and 37 associated with idiopathic epilepsy in the Belgian Shepherd (BS). The locus on chromosome 37 overlap with a locus identified in previous reports 2–4 including a study by our own group 5 . The locus on chromosome 14 has not been published before.…”

Genome-wide association analysis of idiopathic epilepsy in the Belgian shepherd

“…Although the sample size was limited, the cases and controls were robustly defined due to strict criteria applied for phenotypic classification. Previous studies have identified ADAM23 on CFA 37 to be associated with IE in the Belgian shepherd as well as other breeds [ 6 , 16 ]. The significant association of the haplotype block that includes ADAM23 SNPs seen here in a different group of dogs further validated the previous finding and confirmed that the present study cohort was representative of the breed at large.…”

“…Despite epilepsy being the most common neurological condition in dogs [ 5 ], and IE likely having the presence of genetic risk factors, there have been great challenges in identifying the genetic underpinnings of the disorder. It is well understood that in most cases IE is polygenic with particular genotypes contributing to risk [ 4 , 6 – 9 ]. It is also speculated that each affected breed may have its own breed-specific genetic susceptibility profile that interacts with other risk loci that are common across breeds.…”

Man’s best friend in life and death: scientific perspectives and challenges of dog brain banking

“…Epilepsy, for example, is rather common among dogs (general prevalence is 0.5-5.7 %; see [92]), and certain breeds carry an increased risk of epilepsy with prevalence reaching up to 18% [93], indicating the presence of genetic risk factors. Yet, only a few associated polymorphisms have been described so far [94,95]. Studies that could directly investigate alterations in the transcriptomes and metabolomes of affected dogs' brains could be especially useful to pinpoint genetic causes.…”