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GWAS Links Chromosome 37 Locus to Epilepsy in Belgian Shepherds

NEW YORK (GenomeWeb News) – Researchers from Finland, Denmark, Sweden, and the US have identified a chromosome 37 region associated with epilepsy in Belgian Shepherds through a genome-wide association study involving dozens of affected and unaffected dogs.

Though they have not yet tracked down the specific causative gene in the region, the team is using the results of the new study, which appeared online recently in PLoS ONE, as a jumping off point for more detailed sequence-based analyses of the newly identified locus.

"There are only few genes in the identified region and I believe that the ongoing analyses will help us to discover the specific epilepsy gene," corresponding author Hannes Lohi, from the University of Helsinki and the Folkhälsan Institute of Genetics, said in a statement.

Although epilepsy is among the most common neurological problems found in dogs, Lohi and his co-authors explained, its prevalence varies by breed. In Belgian Shepherds, for example, an estimated 20 percent of dogs are affected by epilepsy, making the breed a promising model for studying genetic forms of the condition.

Lohi and his colleagues used Affymetrix 50K arrays to genotype 40 Belgian Shepherds with epilepsy and another 44 dogs from the same breed without epilepsy. The dogs were part of a larger group of 159 affected and 148 unaffected Belgian Shepherds from Finland, Denmark, and the US that are being studied clinically.

Data generated for the discovery group — combined with replication studies on 81 more canine cases and 88 controls — led researchers to a million base stretch of sequence on chromosome 37.

"The identified genomic region is likely to be the strongest single risk factor for epilepsy in Belgian Shepherds," Eija Seppälä, a post-doctoral researcher in Lohi's University of Helsinki lab and the study's first author, said in a statement.

The locus appears to contain at least a dozen genes. None of these genes code for ion channel proteins or other candidates implicated in epilepsy in the past. But two genes in the region — KLF7 and ADAM23 — were selected for further study based on their previously reported roles in neuronal processes.

When they sequenced the exons of both genes in more dogs, researchers found a suspicious non-synonymous variant in ADAM23. The gene codes for a protein that interact with proteins called LGI1 and LGI2, which have been linked to epilepsy in humans or dogs, making it a plausible disease candidate.

Even so, when they genotyped the variant in hundreds more cases and controls, the researchers found that more than one-fifth of Belgian Shepherds without epilepsy are also homozygous for the same ADAM23 allele, suggesting other genetic factors in the region are at play in epilepsy.

Going forward, the team plans to use high-throughput sequencing to comb through the region more carefully and try to find the specific genetic changes causing epilepsy in the dogs.

"[O]ur data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted resequencing study across the locus to identify the causative mutation," the researchers wrote. "It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes, and introduce a novel candidate gene for human idiopathic epilepsies."

Along with follow-up work on the chromosome 37 locus in Belgian Shepherds, the researchers are following up on their findings in affected and unaffected dogs from other breeds and continuing to look for additional genetic regions behind canine epilepsy