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

Abstract

Background Idiopathic epilepsy (IE) is a common neurological disorder in the domestic dog, and is defined as repeated seizure activity having no identifiable underlying cause. Some breeds, such as the Belgian shepherd dog, have a greater prevalence of the disorder. Previous studies in this and other breeds have identified ADAM23 as a gene that confers risk of IE, although additional loci are known to exist. The present study sought to identify additional loci that influence IE in the Belgian shepherd dog. Results Genome-wide association studies (GWAS) revealed a significant association between IE and CFA 14 (p < 1.03 E− 08) and a suggestive association on CFA 37 (p < 2.91 E− 06) in a region in linkage disequilibrium with ADAM23. Logistic regression identified a 2-loci model that demonstrated interaction between the two chromosomal regions that when combined predicted IE risk with high sensitivity. Conclusions Two interacting loci, one each on CFAs 14 and 37, predictive of IE in the Belgian shepherd were identified. The loci are adjacent to potential candidate genes associated with neurological function. Further exploration of the region is warranted to identify causal variants underlying the association. Additionally, although the two loci were very good at predicting IE, they failed to capture all the risk, indicating additional loci or incomplete penetrance are also likely contributing to IE expression in the Belgian shepherd dog.

Risk loci for idiopathic epilepsy in Belgian Shepherd dogs

“…Hence, we were not able to confirm the association between canine chromosome 14 and idiopathic epilepsy, observed by Belanger et al 1 . We suggest that more studies within and across populations should be carried out to clarify if the chromosome 14 locus is a false positive or if different epilepsy‐associated loci segregate in different populations.…”

“…Belanger et al 1 . recently reported the identification of loci on canine chromosome 14 and 37 associated with idiopathic epilepsy in the Belgian Shepherd (BS).…”

“…We reanalyzed the discovery cohort from our original study 5 . This cohort comprised BS from Denmark and Finland and the diagnostic criteria were in line with the criteria used by Belanger et al 1 . The dogs included in our original study were genotyped using a 50K Affymetrix SNP chip leaving 43 378 SNP markers for analysis after genotype quality check.…”

“…The second analysis completely eliminated the chromosome 37 association but no association with markers on chromosome 14 was detected. Belanger et al 1 . found three chromosome 14 markers associated with idiopathic epilepsy, BICF2P1043850, BICF2S2374913 and TIGRP2P191770.…”

Genetic characterization of Addison’s disease in Bearded Collies

“…Logistic regression was used to model the risk of disease as a function of the observed genotypes at each of the four SNPs of interest (CFA11: BICF2G630307993, CFA16: BICF2G630109748, CFA18: BICF2P1230367 and CFA29: BICF2P977298) across the unrelated dogs. Disease probability was defined by methods previously described [ 62 ]. Briefly, the logit of disease probability was modeled as a function of the SNP genotypes representing 3 classes (e.g., AA, AG and GG with 2 degrees of freedom in the analysis).…”