Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis

Abstract

Gamma-aminobutyric acid receptor (GABA-A) is the most common receptor of fast synaptic inhibition in the human brain. Gamma protein encoded by the GABRG2 gene is one of the subunits of the GABA-A receptor, which plays an essential role in the function of this receptor. Several studies have identified various febrile seizure (FS) and epilepsy risk variants of GABRG2 gene in different populations, but some others did not support these results. The aim of this case-control study is to investigate whether GABRG2 polymorphisms contribute to susceptibility for FS and epilepsy in pooled data of three cohorts, from Malaysia (composed of Malay, Chinese, and Indian), Hong Kong, and Korea. Furthermore, the pooled dataset of these cohorts with previous reports were meta-analyzed for determining the risk effect size of the rs211037 polymorphism on FS and symptomatic epilepsy (SE). The rs211037, rs210987, rs440218, rs2422106, rs211014, and rs401750 polymorphisms were genotyped in the 6442 subjects (1729 epilepsy and 4713 controls). Results of the case-control study showed associations between rs211037 and the risk of SE in the pooled data from all cohorts (T vs. C, p = 3 × 10(-5), and TT vs. CC, p = 2 × 10(-5)) and the risk of partial seizure in the combined data of Malaysia and Hong Kong (both T vs. C and TT vs. CC, p = 2 × 10(-6)). The rs211037-rs210987 and rs2422106-rs211014-rs401750 haplotypes were also associated with susceptibility to SE in Chinese. Meta-analysis of all Asians identified association between rs211037 and FS and SE (T vs. C, p = 4 × 10(-4), and p = 4 × 10(-3), respectively). In conclusion, rs211037 alone may be a risk factor for FS, partial seizure, and SE, and in linkage disequilibrium with rs210987 can contribute to FS and SE in Asians, particularly in Chinese.

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

“…11). Interestingly, TNF, whose transcription was not altered upon knockdown of Arc, regulates 15 genes (Table 7), the top five of which are Casp8 (neuroinflammation) 97 , Ptgs2 (also regulated by APP and CREB1), Gabrg2 (neuroinflammation) 98,99 , Bdnf (synaptogenesis; neuroinflammation, AD progression) [100][101][102][103] and Penk (opioid signaling, AD progression) 104 . While the top CREB1-regulated genes are mainly associated with the opioid signaling pathway, APP and TNF are implicated in neuroinflammation.…”

Anthropogenetic Variability in the Group of Individuals with Febrile Seizures: Population-Genetic Study

“…The etiology of FS is complex and it is still the subject of numerous studies and research done in the field. However, there is strong evidence showing that heterogeneous genetic predisposition interacting with various risk factors can lead to a FS [ 6 , 7 ].…”

Interactions between GHRH and GABAARs in the brains of patients with epilepsy and in animal models of epilepsy

“…GABAARs are the most important part of inhibitory neurotransmission in the brain and are composed of the following subunits: α1–6, β1–3, γ1–3, δ, ε, π, θ, and ρ1–3, among which, the α1–3, β2–3 and γ2 subunit compositions of five dimers play a major role 6 , 27 . Changes in the expression of these subunits and alterations in the function of the receptor induced by mutation, tumors or hypoxia may interfere with inhibitory transmission by GABAARs, resulting in epilepsy 15 , 28 . For example, the alpha 1 subunit D219N mutation has been identified in patients with idiopathic generalized epilepsy 29 , and an A322D mutation was detected in patients with juvenile myoclonic epilepsy 30 .…”

“…Epilepsy was previously shown to mainly cause neuronal hyperexcitability in the brain, which results from the imbalance between excitation and inhibition mediated by glutamate and GABA, respectively 15 , 16 . A reduction in GABAergic interneuron activity weakens its suppressive function, thereby increasing the occurrence of spontaneous seizures and promoting the progression of TLE 17 .…”