title: High-density SNP screen of sodium channel genes by haplotype tagging and DNA pooling for association with idiopathic generalized epilepsy.
abstract: We have investigated seven voltage-gated sodium channel genes for association with idiopathic generalized epilepsy (IGE). Probands and control DNA were grouped into pools and used to screen 85 single-nucleotide polymorphisms (SNPs), mostly HapMap SNPs tagging the common variation in these genes. Twelve SNPs exhibiting an allele frequency difference between pools were genotyped individually in our sample of 232 probands, 313 controls, and 95 parent-proband trios. Two SNPs, in SCN1A and SCN8A, were associated by allele and genotype at nominal level of significance, but were not significant after Bonferroni correction. Two SCN2A SNPs (rs3943809 and rs16850331) were associated by case-control with a subgroup with IGE and history of febrile seizures and also by transmission disequilibrium test (TDT) in parent-proband trios. Both SNPs are part of a linkage disequilibrium (LD) cluster of 38 SNPs, but none are obvious functional variants. The association of rs3943809 with the febrile seizure subgroup (p = 0.0004) remains significant after the conservative Bonferroni correction for multiple testing.
authors.affiliation: Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, de Crespigny Park, Denmark Hill, London, United Kingdom. a.makoff@iop.kcl.ac.uk
authors.forename: Andrew
authors.initials: A
authors.lastname: Makoff
authors.forename: Teck
authors.initials: T
authors.lastname: Lai
authors.forename: Catherine
authors.initials: C
authors.lastname: Barratt
authors.forename: Antonio
authors.initials: A
authors.lastname: Valentin
authors.forename: Nick
authors.initials: N
authors.lastname: Moran
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.forename: Lina
authors.initials: L
authors.lastname: Nashef
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D004829:Epilepsy, Generalized / Q000175:diagnosis / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D003294:Seizures, Febrile / Q000175:diagnosis / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C100681:SCN8A protein, human; D015222:Sodium Channels