title: Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy.
abstract: Idiopathic generalised epilepsy (IGE) is a common form of epilepsy, including several defined and overlapping syndromes, and likely to be due to the combined actions of mutations in several genes. In a recent study we investigated the calcium channel gene CACNA1A for involvement in IGE, unselected for syndrome, by means of association studies using several polymorphisms within the gene. We reported a highly significant case/control association with a silent single nucleotide polymorphism (SNP) in exon 8 that we confirmed by within-family analyses. In this present study we screened the gene for novel SNPs within 25 kb of exon 8, which have enabled us to define the critical region of CACNA1A in predisposing to IGE. Several intronic SNPs were identified and three, within 1.5 kb of exon 8 and in strong linkage disequilibrium with each other and with the original SNP, were significantly associated with IGE (P=0.00029, P=0.0015 and P=0.010). The associations were not limited to an IGE syndrome or other subgroup. Another SNP, 25 kb away, in intron 6 was also significantly associated with IGE (P=0.0057) but is not in linkage disequilibrium with the SNPs around exon 8. Haplotype predictions revealed even more significant associations (3-marker haplotype: P<10(-6)). Logistic regression showed that all the data can be explained by two of the SNPs, which is consistent with two functionally significant variants being responsible for all five associations, although a single variant cannot be excluded. The functionally significant variant(s) are unlikely to be exonic and suggests an effect on expression or alternative splicing.
authors.affiliation: Department of Psychological Medicine, Institute of Psychiatry, London SE5 8AF, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Chioza
authors.forename: Abena
authors.initials: A
authors.lastname: Osei-Lah
authors.forename: Lina
authors.initials: L
authors.lastname: Nashef
authors.forename: Blanca
authors.initials: B
authors.lastname: Suarez-Merino
authors.forename: Hazel
authors.initials: H
authors.lastname: Wilkie
authors.forename: Pak
authors.initials: P
authors.lastname: Sham
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Makoff
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type