Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and susceptibility to idiopathic generalized epilepsy

Several interacting genetic factors are likely to be involved in the epilep togenesis of idiopathic generalized epilepsies (IGE). Neurotransmitter tran sporters play a central role in the fine tuning of neurotransmission by rem oval of released neurotransmitters from the synaptic cleft. The present ass ociation study tested the hypotheses that variation of the genes encoding n eurotransmitter transporters confers susceptibility to IGE. The genotypes o f 133 German IGE subjects and 223 ethnically matched controls were assessed for DNA polymorphisms of genes encoding the glutamate (EAAT2), the seroton in (SERT), and dopamine (DAT) transporters. To increase genetic homogeneity , a subgroup of 76 patients with idiopathic absence epilepsy (IAE) was anal yzed separately. We found no evidence for an allelic association of either the silent G603A substitution polymorphism in exon 5 of the EAAT2 gene or t he regulatory promoter polymorphism of the SERT gene with either IGE or IAE . The frequency of the nine-copy allele of the 40 base pair repeat polymorp hism in the 3' un pop popd region of the DAT gene was significantly increas ed in the IGE patients (chi(2) = 4.11, degrees of freedom (d.f.) = 1, P = 0 .043) and, in particular, in the IAE patients (chi(2) = 7.81. d.f. = 1, P = 0.005) compared with the controls. The present findings strengthen previou s evidence that genetic variation of the DAT gene modulates neuronal networ k excitability and contributes to the epileptogenesis of IAE. (C) 2000 Publ ished by Elsevier Science B.V. All rights reserved.