title: Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility.
abstract: OBJECTIVE
  Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study.
  
  
  METHODS
  We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry.
  
  
  RESULTS
  SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82.
  
  
  CONCLUSIONS
  The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB-120, Philadelphia, PA 19104-6140, USA. rjbuono@mail.med.upenn.edu
authors.forename: R J
authors.initials: RJ
authors.lastname: Buono
authors.forename: F W
authors.initials: FW
authors.lastname: Lohoff
authors.forename: T
authors.initials: T
authors.lastname: Sander
authors.forename: M R
authors.initials: MR
authors.lastname: Sperling
authors.forename: M J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: D J
authors.initials: DJ
authors.lastname: Dlugos
authors.forename: S G
authors.initials: SG
authors.lastname: Ryan
authors.forename: G T
authors.initials: GT
authors.lastname: Golden
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: T M
authors.initials: TM
authors.lastname: Scattergood
authors.forename: W H
authors.initials: WH
authors.lastname: Berrettini
authors.forename: T N
authors.initials: TN
authors.lastname: Ferraro
mesh_terms: D016009:Chi-Square Distribution; D016001:Confidence Intervals; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016017:Odds Ratio; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D040641:Quantitative Trait Loci / Q000235:genetics; D012640:Seizures / Q000235:genetics*; D000098854:Kcnj10 Channel
chemical_list: D000098854:Kcnj10 Channel; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying