GABAA receptor polymorphisms in alcohol use disorder in the GWAS era

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing, neuro-psychiatric illness of high prevalence and with a serious public health impact worldwide. It is complex and polygenic, with a heritability of about 50%, and influenced by environmental causal heterogeneity. Risk factors associated with its etiology have a genetic component. GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in mammalian brain. GABA receptors are believed to mediate some of the physiological and behavioral actions of alcohol. In this critical review, relevant genetic terms and type and methodology of the genetic studies are briefly explained. Postulated candidate genes that encode subunits of GABA receptors, with all the reported SNPs, are presented. Genetic studies and meta-analyses examining polymorphisms of the GABA receptor and their association with AUD predisposition are presented. The data are critically examined with reference to recent GWAS studies that failed to show relations between GABA receptors and AUD. Restrictions and perspectives of the different findings are discussed.

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

“…When compared with δ-containing GABA A receptors, γ2-containing GABA A receptors are extensively expressed throughout the brain 34 . Clinically, there is some evidence that alterations to Gabrg2 is related to the propensity to develop alcoholism 35–37 and past work has shown γ2-subunit containing receptors respond to high concentrations of alcohol (>30–40 mM 31 ). This indicates that γ2-containing GABA A receptors are less sensitive to alcohol—especially relative to those with a δ subunit.…”

Determination of the Appropriate Kernel Structure in Electroencephalography Analysis of Alcoholic Subjects

“…Alcohol depresses neurons by stimulating GABA, forming a complex with the GABA receptor, and inhibiting the release of noradrenaline from the locus coeruleus. This event can explain the depressing effect of alcohol by GABA mechanism [1,4,5].…”

α6-Containing GABAAReceptors: Functional Roles and Therapeutic Potentials

“…A direct contribution of a6GABA A Rs to disorders associated with the GABRA6 rs3219151 C variants is supported by the finding that the 3 0 UTR of mRNAs is the binding target of microRNAs (miRNAs) and RNA binding proteins that regulate mRNA levels in specific subcellular regions and determine the intensity of gene repression (Koulentaki and Kouroumalis, 2018). Binding of miRNAs to the 3 0 UTR cause mRNA cleavage or translation repression and thus elicit a reduced gene expression.…”