Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy
AU - Chioza, Barry
AU - Osei-Lah, Abena
AU - Nashef, Lina
AU - Suarez-Merino, Blanca
AU - Wilkie, Hazel
AU - Sham, Pak
AU - Knight, Jo
AU - Asherson, Philip
AU - Makoff, Andrew J
PY - 2002/12
Y1 - 2002/12
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Base Sequence
KW - Calcium Channels
KW - Child
KW - Child, Preschool
KW - Chromatography, High Pressure Liquid
KW - DNA Mutational Analysis
KW - Epilepsy, Generalized
KW - Female
KW - Gene Frequency
KW - Haplotypes
KW - Humans
KW - Linkage Disequilibrium
KW - Male
KW - Middle Aged
KW - Molecular Sequence Data
U2 - 10.1038/sj.ejhg.5200896
DO - 10.1038/sj.ejhg.5200896
M3 - Journal article
C2 - 12461694
VL - 10
SP - 857
EP - 864
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 12
ER -