Genome-wide linkage scan for loci associated with epilepsy in Belgian shepherd dogs

The present study was conducted to analyze the genetic characteristics of the Donggyeong dog and establish parentage conservation systems for it by using 10 microsatellite markers recommended by the International Society for Animal Genetics (ISAG). A total of 369 dogs from 12 dog breeds including the Donggyeong dog were genotyped using 10 microsatellite loci. The number of alleles per locus varied from 5 to 10 with a mean value of 7.6 in the Donggyeong dog. The observed heterozygosity and expected heterozygosity ranged from 0.4706 to 0.9020 (mean 0.7657) and from 0.4303 to 0.8394 (mean 0.7266), respectively. The total exclusion probability of 10 microsatellite loci was 0.99955. Of the 10 microsatellite markers, the AHT121, AHTh260 and CXX279 markers had relatively high PIC values (≥0.7). This study found that there were specific alleles, 116 allele at AHT121 in the Donggyeong dog when compared with other dog breeds. Also, the results showed two (Korean native dogs and the foreign dog breeds) distinct clusters. The closest distance (0.1184) was observed between the Donggyeong dog and Jindo dog, and the longest distance (0.3435) was observed between the Donggyeong dog and Bulgae. The Korean native dog breeds have comparatively near genetic distances between each other.

show abstract

“…Heterozygosity increases when the percentage of mutations is high, or when the size of the group becomes larger [16]. …”

Section: Discussionmentioning

confidence: 99%

Molecular Genetic Diversity of the Gyeongju Donggyeong Dog in Korea

2014

View full text Add to dashboard Cite

show abstract

“…The first microsatellite-based approach suggested six loci on CFAs 2, 6, 12 and 37 [15]. Genome-wide significance was later confirmed only at CFA37 by a low density genome-wide association study (GWAS) and finemapping with roughly 100 cases and 100 controls [14].…”

Section: Introductionmentioning

confidence: 99%

Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene

et al. 2015

View full text Add to dashboard Cite

BackgroundIdiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37.ResultsWe have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (pc = 2.9e–07, pGWAS = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (praw = 2.76e–15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49–0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy.ConclusionsThese results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1651-9) contains supplementary material, which is available to authorized users.

show abstract

“…Despite efforts using either candidate gene [34] or low-resolution genome wide approaches [35], [36], the genetic background of many focal and generalized epilepsies remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Various pedigree analyses have suggested different modes of inheritance from simple recessive to polygenic with a major gene or a gene with incomplete penetrance [7], [18], [35], [36]. A recent microsatellite-based genome wide linkage scan with 366 dogs including 74 cases identified six tentative loci on four chromosomes, although none of them reached a genome-wide significance [36]. This could indicate genetic or phenotypic heterogeneity of epilepsy in BS.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

et al. 2012

View full text Add to dashboard Cite

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10−10, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10−8, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10−11, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. 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.

show abstract

Genome-wide linkage scan for loci associated with epilepsy in Belgian shepherd dogs

Cited by 20 publications

References 40 publications

Molecular Genetic Diversity of the Gyeongju Donggyeong Dog in Korea

Molecular Genetic Diversity of the Gyeongju Donggyeong Dog in Korea

Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

Contact Info

Product

Resources

About