Abstract
Variations in genes encoding several GABAA receptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between GABRB1, the gene encoding GABAA receptor β1 subunits, with Alcohol dependence (AD), both on its own and comorbid with other substance dependence and psychiatric illnesses. In the present study, we hypothesized that the GABRB1 genetically-associated increased risk for developing alcoholism may be associated with impaired behavioral control and altered sensitivity to reward, as a consequence of altered brain function. Exploiting the IMAGEN database (Schumann et al., 2010), we explored in a human adolescent population whether possession of the minor (T) variant of the single nucleotide polymorphism (SNP) rs2044081 is associated with performance of tasks measuring aspects of impulsivity, and reward sensitivity that are implicated in drug and alcohol abuse. Allelic variation did not associate with altered performance in either a stop-signal task (SST), measuring one aspect of impulsivity, or a monetary incentive delay (MID) task assessing reward anticipation. However, increased functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) response in the right hemisphere inferior frontal gyrus (IFG), left hemisphere caudate/insula and left hemisphere inferior temporal gyrus (ITG) during MID performance was higher in the minor (T) allelic group. In contrast, during SST performance, the BOLD response found in the right hemisphere supramarginal gyrus, right hemisphere lingual and left hemisphere inferior parietal gyrus indicated reduced responses in the minor genotype. We suggest that β1-containing GABAA receptors may play a role in excitability of brain regions important in controlling reward-related behavior, which may contribute to susceptibility to addictive behavior.
Highlights
Alcohol dependence (AD) is a complex, heterogeneous disease with both strong genetic and environmental influences in its etiology
Pre-existing data collected from 1299 participants under the IMAGEN project were used to test a hypothesis that variations in the rs2044081 single nucleotide polymorphisms (SNPs) of GABRB1 are associated with altered brain activity during performance of tasks implicated in the development of addictive behavior
Ethnicity information was missing from four participants in the entire sample, three of which were participants that were included in the sub-group that completed the stop-signal task (SST)
Summary
Alcohol dependence (AD) is a complex, heterogeneous disease with both strong genetic and environmental influences in its etiology. A number of genes encoding subunits of GABAA receptors have been associated with both AD and addiction to other drugs (for a review see Stephens et al, 2017). Genes encoding many of the GABAA subunits are organized into chromosomal clusters. GABRA2, GABRA4, GABRB1 and GABRG1, encoding for α2, α4, β1, γ1 subunits, respectively, are localized on chromosome 4p12 (Song et al, 2003). Gene association studies have consistently identified single nucleotide polymorphisms (SNPs) and haplotypes in this region to be associated with both alcohol and other drug addictions. An association has been identified between the intergenic SNP rs2044081 in GABRB1 and AD in a large (611 cases, 646 controls), well characterized British/Irish population (Odds Ratio 4.2 (95% Confidence Intervals 1.5–11.5) Pcorrected 3.31 × 102; McCabe et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
