The Effects of Variation in the GABA Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus.

BACKGROUND

γ-aminobutyric acid (GABA) and its main receptor, the GABA receptor, are implicated in major depressive disorder (MDD). Anxious depression (AD) is deemed to be a primary subtype of MDD. The amygdala and the dorsolateral prefrontal cortex (DLPFC) are key brain regions involved in emotional regulation. These regions contain the most GABA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABA receptor gene polymorphisms affect the functions of specific brain regions, in particular, the amygdala and the DLPFC.

METHODS

The sample comprised 83 patients with AD, 70 patients with non-anxious depression (NAD), and 62 healthy controls (HC). All participants underwent genotyping for polymorphisms of GABA receptor subunit genes, followed by a resting-state fMRI scan. The HAMD-17 was used to evaluate the severity of MDD. ANOVA was performed to obtain the difference in the imaging data, GABA receptor multi-locus genetic profile scores (MGPS), and HAMD-17 scores among three groups, then the significant differences between AD and NAD groups were identified. Mediating effect analysis was used to explore the role of functional connectivity (FC) between the amygdala and DLPFC in the association between the GABA receptor gene MGPS and AD clinical features.

RESULTS

Compared with the NAD group, the AD group had a higher GABA receptor MGPS. AD patients exhibited a negative correlation between the MGPS and FC of the right centromedial (CM) subregion, and the right middle frontal gyrus (MFG). A negative correlation was also observed between the MGPS and anxiety/somatic symptoms. More importantly, the right CM and right MFG connectivity mediated the association between the GABA receptor MGPS and anxiety/somatic symptoms in patients with AD.

CONCLUSION

The decreased FC between the right MFG and right CM subregion mediates the association between GABA receptor MGPS and AD.