Genetic variability in glutamic acid decarboxylase genes: associations with post-traumatic seizures after severe TBI

Abstract

Post traumatic seizures (PTS) occur frequently after traumatic brain injury (TBI). Since gamma-amino butyric acid (GABA) neurotransmission is central to excitotoxicity and seizure development across multiple models, we investigated how genetic variability for glutamic acid decarboxylase (GAD) influences risk for PTS. Using both a tagging and functional single nucleotide polymorphism (SNP) approach, we genotyped the GAD1 and GAD2 genes and linked them with PTS data, regarding time to first seizure, obtained for 257 adult subjects with severe TBI. No significant associations were found for GAD2. In the GAD1 gene, the tagging SNP (tSNP) rs3828275 was associated with an increased risk for PTS occurring <1 wk. The tSNP rs769391 and the functional SNP rs3791878 in the GAD1 gene were associated with increased PTS risk occurring 1 wk-6 mo post-injury. Both risk variants conferred an increased susceptibility to PTS compared to subjects with 0-1 risk variant. Also, those with haplotypes having both risk variants had a higher PTS risk 1 wk-6 mo post-injury than those without these haplotypes. Similarly, diplotype analysis showed those with 2 copies of the haplotype containing both risk alleles were at the highest PTS risk. These results implicate genetic variability within the GABA system in modulating the development of PTS.

Copyright © 2012 Elsevier B.V. All rights reserved.

Figures

Figure 1. SNP Associations for PTS

Rs3828275 genotype was associated with lower PTS

Figure 2. SNP Associations with PTS 1 wk-6 mo post-TBI

(A) rs3791878 associated with PTS in the 1wk-6 mo post-TBI period (p=0.05); population sizes by genotype GG=75, GT=60, TT=18. (B) rs769391 associated with PTS in the 1wk-6 mo post-TBI period (p=0.094) (population sizes by genotype GG=16, AG=54, AA=89). (C) Number of risk variants associated with PTS in the 1wk-6 mo post-TBI period (p=0.019); population sizes by number of risk genotypes zero=58, one=24, two=67.

Figure 3. Haplotype and Diplotype Associations with PTS 1 wk-6 mo post-TBI

(A) Haplotypes with both risk variants associated with PTS 1wk-6mo post-TBI (p=0.033); population sizes by number of variants without both=119 with both=207. (B) Two haplotypes with both risk variants associated with PTS 1wk-6 mo post-TBI (p=0.038), population sizes by number of haplotypes with both risk variants zero=26 one=66 two=71. (C) Two haplotypes with both risk variants associated with PTS 1wk-6 mo post-TBI (p=0.015); population sizes by number of haplotypes with both risk variants: zero or one=92, two=71.