title: Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.
abstract: BACKGROUND
  The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy.
  
  
  METHODS
  We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy.
  
  
  RESULTS
  We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable.
  
  
  CONCLUSIONS
  The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.
authors.affiliation: Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland Research Institute, and Division of Neurology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Rinki
authors.initials: R
authors.lastname: Singh
authors.forename: John M
authors.initials: JM
authors.lastname: Lynch
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Grinton
authors.forename: Cassandra
authors.initials: C
authors.lastname: Szoeke
authors.forename: Kevin
authors.initials: K
authors.lastname: Murphy
authors.forename: Peter
authors.initials: P
authors.lastname: Kinirons
authors.forename: Deirdre
authors.initials: D
authors.lastname: O'Rourke
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Chantal
authors.initials: C
authors.lastname: Depondt
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Curtis
authors.initials: C
authors.lastname: Gumbs
authors.forename: Nicole
authors.initials: N
authors.lastname: Walley
authors.forename: James
authors.initials: J
authors.lastname: McNamara
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Linney
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Sheffield
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Radtke
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tate
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Chissoe
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: David
authors.initials: D
authors.lastname: Hosford
authors.forename: Alice
authors.initials: A
authors.lastname: Stanton
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Graves
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.forename: Kai
authors.initials: K
authors.lastname: Eriksson
authors.forename: Anne-Mari
authors.initials: AM
authors.lastname: Kantanen
authors.forename: Reetta
authors.initials: R
authors.lastname: Kalviainen
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Josemir W
authors.initials: JW
authors.lastname: Sander
authors.forename: John S
authors.initials: JS
authors.lastname: Duncan
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Colin P
authors.initials: CP
authors.lastname: Doherty
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015331:Cohort Studies; D004827:Epilepsy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000235:genetics; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B / Q000235:genetics; D012640:Seizures / Q000235:genetics*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000235:genetics; D016704:Synapsins / Q000235:genetics; D013577:Syndrome
chemical_list: C106350:GABRR2 protein, human; C097044:KCNAB1 protein, human; C410183:KCNMB4 protein, human; D051664:Kv1.3 Potassium Channel; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D016704:Synapsins; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase