A Polymorphism in GAD65 Modulates Anxiety Vulnerability in Women

What's the science?

Anxiety disorders are common and debilitating and occur more frequently in women. Understanding the brain chemistry and genetic predisposition to anxiety will be critical for developing treatments. A brain region called the pregenual anterior cingulate cortex is known to be involved in anxiety and to regulate amygdala activity (another brain region involved in anxiety and emotion). The balance of neurotransmitters, GABA (inhibitory) and glutamate (excitatory), in the pregenual anterior cingulate is thought to be important for modulating brain activity and anxiety. Different genetics affecting the synthesis of GABA in the brain could affect anxiety, however this is not yet clear. This week in The Journal of Neuroscience, Colic and colleagues test whether a genetic polymorphism (change in the code of a gene) can alter GABA levels in the brain and also influence brain activity and anxiety.

How did they do it?

They sorted 105 healthy participants (mean age = 27) into two groups based on their genotype for the GAD65 gene (carriers vs. non-carriers of a G allele) which is responsible for GABA synthesis. Carriers of the G allele of this genotype are associated with drastic increases in GABA transcription (production) in peripheral cells. They scanned the participants (mean age of 27) using an imaging technique called MR Spectroscopy which can measure GABA/glutamate neurotransmitter ratios in the brain. They used resting state fMRI to measure brain activity at rest in the pregenual anterior cingulate cortex of these participants. They then tested a) the effect of genotype on brain activity, b) GABA/glutamate levels and c) whether there was any genotype by sex interaction (whether genotype affects these brain measures depending on sex) d) whether measured vulnerability to anxiety using a harm avoidance scale (correlates with anxiety) from the Temperament and Character Inventory was correlated with these brain measures.

What did they find?

Resting brain activity in the pregenual anterior cingulate was significantly lower in carriers of the G allele, but there was no interaction effect of GAD65 or sex on brain activity. However, there was a significant interaction between sex and genotype in the pregenual anterior cingulate on GABA/ glutamate levels, with female G allele carriers showing higher GABA levels. The level of reported harm avoidance was negatively correlated with the level of GABA in the pregenual anterior cingulate cortex in females (and not in males), suggesting that the lower GABA could be underlying anxiety vulnerability in females. To confirm the relationships between genotype, brain activity, GABA and harm avoidance they performed a ‘moderated mediation analysis’ including genotype as a predictor and harm avoidance as an outcome, brain activity and GABA as mediators, and sex as a moderator. Genotype significantly predicted harm avoidance, mediated by GABA/ glutamate levels in females only.

                                     Brain,  S  ervier Medical Art,  image by BrainPost,  CC BY-SA 3.0

                                     Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

This is the first study to show that a polymorphism in a gene producing GABA is associated with differences in GABA levels in the brain. Further, these polymorphisms affect anxiety in females (not in males), and this relationship is mediated by GABA levels in the brain. This study highlights the importance of studying genetic differences that could influence brain chemistry or activity and that these differences may differ depending on sex. We now know that female vulnerability to anxiety could be related to genetic predisposition and inhibitory neurotransmitter levels in the pregenual anterior cingulate cortex.


Colic et al., GAD65 promoter polymorphism rs2236418 modulates harm avoidance in women via inhibition/excitation balance in the rostral ACC. The Journal of Neuroscience (2018). Access the original scientific publication here.