Association analysis of GABA A β2 and γ2 gene polymorphisms with event-related prefrontal activity in man

Abstract

Gamma-aminobutyric acid (GABA)A-receptors play a crucial role in the generation of electroencephalogram (EEG) oscillations and evoked potentials (ERPs). The present association study was designed to test whether EEG and ERPs are modulated by genetic variations of the human GABAA beta2 (GABRB2) and gamma2 (GABRG2) genes on chromosome 5q33. The genotypes of two nucleotide substitution polymorphisms of the GABRB2 and GABRG2 genes were assessed in 95 psychiatrically healthy subjects of German descent. Neurophysiological phenotyping was performed with four factorized EEG/ERP parameters: EEG activation, anterior and posterior EEG synchronization, and event-related activity (N100/ P200-complex). No genotypic association was found for the GABRB2 nucleotide exchange polymorphism with any electrophysiological parameter. A significant association was found between the genotype of the intronic GABRG2 G-->A nucleotide exchange and the event-related N100/P200 (ANOVA: F=3.81; df=2; P=0.026). A comparison of homozygous subjects carrying either the G/G or A/A genotype of the GABRG2 polymorphism consistently revealed an even stronger difference in the effect-size (ANOVA: F=11.13; df=1; P=0.002). Post hoc analysis of this association with current density analysis in three-dimensional neuroanatomic Talairach space-time showed a reduction in the event-related signal power after 120 ms in the right dorsolateral prefrontal cortex. Taking into account the risk of false-positive association findings attributable to multiple testing, our results encourage further replication studies to examine the phenotype-genotype relationship of GABRG2 gene variants and event-related prefrontal activity.

Association of EEG coherence and an exonic GABABR1 gene polymorphism

“…Also, this dependency on the physiological condition is in line with pharmacological investigations that rather suggest GABA A receptors to contribute to phasic synchronization [Winterer et al, 2000a,b]. Actually, the physiological evidence that phasic synchronization is more closely related to GABA A receptor activation and that GABA B receptor activation is more likely to result in tonic synchronization, led to the application of only the two tonic synchronization measures (i.e., frontal and parietotemporal coherence) instead of using four phenotypic measures as in the previous study [Winterer et al, 2000a]. However, it needs to be mentioned at this point that a recent study, which was published after our paper was submitted, did report significant linkage and linkage disequilibrium of resting-EEG beta activity and a set of GABA A receptor genes on chromosome 4 [Porjesz et al, 2002].…”

“…In other words, coherence measurements detect particular pairs of synchronized oscillators within the network of cortically distributed oscillators [Nunez et al, 1997[Nunez et al, , 1999]. An imbalance between the GABAergic and glutamatergic system may account for variations of coherences since both neurotransmitter systems are critical to the function of the local inhibitory circuits, which are in turn essential for cortical synchronization, i.e., coherent activity [Traub and Miles, 1991;Whittington et al, 1995Whittington et al, , 1997Steriade et al, 1996;Winterer et al, 2000a].…”

“…These three DNA sequence polymorphisms provide the tools to conduct an association study for EEG coherence as a function of genotype. Coherence measures were chosen for this investigation because they reflect tonic cortical synchronization rather than transient, e.g., event-related synchronization, which may be under stronger control of GABA A receptors as previously reported [Winterer et al, 2000a].…”

Association Analysis of γ2 Subunit of γ-Aminobutyric Acid Type A Receptor Polymorphisms with Febrile Seizures

“…Two synonymous polymorphic repeat markers have been identified in single-nucleotide polymorphism (17): the G3 A nucleotide exchange at nucleotide position 3145 in the intronic sequence, and SNP211037 (Asn196Asn), at nucleotide position 588, allowing researchers to detect disease-causing gene association.…”

Haplotype association between GABAA receptor γ2 subunit gene (GABRG2) and methamphetamine use disorder

“…. 37 Thus, the prefrontal activation difference may reflect the differential GABRG2 activities derived from variants of the gene. Accordingly, GABRG2 activities in PFC could affect the modulation of mesolimbic reward circuitries, which might be associated with vulnerability of METH use disorder.…”