title: Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene.
abstract: BACKGROUND
  Idiopathic 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.
  
  
  RESULTS
  We 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 (p(c) = 2.9e-07, p(GWAS) = 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 (p(raw) = 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. lotta.koskinen@helsinki.fi.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. lotta.koskinen@helsinki.fi.|Folkhälsan Institute of Genetics, Helsinki, Finland. lotta.koskinen@helsinki.fi.
authors.forename: Lotta L E
authors.initials: LL
authors.lastname: Koskinen
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. eija.seppala@blueprintgenetics.com.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. eija.seppala@blueprintgenetics.com.|Folkhälsan Institute of Genetics, Helsinki, Finland. eija.seppala@blueprintgenetics.com.
authors.forename: Eija H
authors.initials: EH
authors.lastname: Seppälä
authors.affiliation: Department of Animal Science, University of California Davis, Davis, California, USA. jmbelanger@ucdavis.edu.
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Belanger
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. meharji.arumilli@helsinki.fi.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. meharji.arumilli@helsinki.fi.|Folkhälsan Institute of Genetics, Helsinki, Finland. meharji.arumilli@helsinki.fi.
authors.forename: Meharji
authors.initials: M
authors.lastname: Arumilli
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. osmo.hakosalo@helsinki.fi.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. osmo.hakosalo@helsinki.fi.|Folkhälsan Institute of Genetics, Helsinki, Finland. osmo.hakosalo@helsinki.fi.
authors.forename: Osmo
authors.initials: O
authors.lastname: Hakosalo
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. pzjokine@gmail.com.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. pzjokine@gmail.com.|Folkhälsan Institute of Genetics, Helsinki, Finland. pzjokine@gmail.com.
authors.forename: Päivi
authors.initials: P
authors.lastname: Jokinen
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. elisanevalainen@gmail.com.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. elisanevalainen@gmail.com.|Folkhälsan Institute of Genetics, Helsinki, Finland. elisanevalainen@gmail.com.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Nevalainen
authors.affiliation: Department of Clinical Veterinary Sciences, University of Helsinki, Helsinki, Finland. ranno.viitmaa@helsinki.fi.
authors.forename: Ranno
authors.initials: R
authors.lastname: Viitmaa
authors.affiliation: Department of Clinical Veterinary Sciences, University of Helsinki, Helsinki, Finland. tarja.jokinen@helsinki.fi.
authors.forename: Tarja S
authors.initials: TS
authors.lastname: Jokinen
authors.affiliation: Department of Animal Science, University of California Davis, Davis, California, USA. amoberbauer@ucdavis.edu.
authors.forename: Anita M
authors.initials: AM
authors.lastname: Oberbauer
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. hannes.lohi@helsinki.fi.|Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland. hannes.lohi@helsinki.fi.|Folkhälsan Institute of Genetics, Helsinki, Finland. hannes.lohi@helsinki.fi.
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000818:Animals; D004283:Dog Diseases / Q000209:etiology* / Q000235:genetics*; D004285:Dogs; D004827:Epilepsy / Q000209:etiology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D012306:Risk
chemical_list: D051722:ADAM Proteins