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: P510 76 ). 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.

Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies

“…Ninety-eight percent of them clearly define the study population[34–78,80–83]. In relation to representativeness of the controls, fifty-six percent were either population–based or healthy volunteers[36,38–42,45,46,48,51–53,55,58,62–65,67,69–72,74,77,80,82,83] and forty-five percent were both population-based and hospital-based/healthy volunteers/blood donors[34,35,37,43,44,47,49,50,54,56,57,59–61,66,68,73,75,76,78,79,81]. Sixty four percent of control matched only one variable (age, gender or ethnicity) with cases[36–40,42–48,50–54,56,57,62,66,68,69,71,73,75–79,81,82].…”

“…Ninety-two percent clearly described diagnosis for JME[35–53,55–78,80,82,83]. Seventy-eight percent of the studies had sample size larger than 200 (number of cases and controls)[38–41,43–68,70–73,76–79,82]. The majority (80%) did not perform genotyping under “blind” conditions (or did not mentioned this aspect).…”

“…The majority (80%) did not perform genotyping under “blind” conditions (or did not mentioned this aspect). Results of HWE analysis were reported in 70% of the studies[36–41,43,45–47,49–53,55,56,58–60,62–65,67–72,74,76–78,82]. Ninety percent of the studies assessed the association between genotypes and JME using X 2 test and logistic regression, according to Clarke et al[84][34–39,41–53,55–68,70–78,80–82].…”

“…Our review provides an updated perspective on the accumulating evidence on common susceptibility alleles in this IGE subtype. In the 50 association studies reviewed, most polymorphisms were examined in one case–control study, of which just 17% had a positive association[34,43,47–49,51–53,55,58,61,62,64,66–69,71,77,80–83]. However, taking into account the high a priori risk of false positive results in candidate gene association studies[25], a discussion of the biological significance of these cases was precluded.…”

Migraine genetics: An update

“…Of four single nucleotide polymorphisms (SNPs) and one microsatellite marker located within the CACNA1A gene, one SNP in exon 8 showed a significant association. Follow-up study showed that two SNPs in the immediate vicinity of exon 8 were responsible for the association with epilepsy [58]. The association was not limited to a specific epileptic syndrome or subgroup.…”