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

Juan Qiao,1,2 Shiwan Tao,2 Yurong Sun,3,4 Jiabo Shi,2,5 Yu Chen,2,5 Shui Tian,3,4 Zhijian Yao,2,5 Qing Lu3,4 1Department of Psychology, Xuzhou East Hospital Affiliated to Xuzhou Medical University, Xuzhou, People’s Republic of China; 2Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, People’s Republic of China; 3School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, People’s Republic of China; 4Key Laboratory of Child Development and Learning Science, Ministry of Education, Nanjing, People’s Republic of China; 5Nanjing Brain Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of ChinaCorrespondence: Zhijian Yao, Department of Psychiatry, Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, People’s Republic of China, Email [email protected] Qing Lu, Email [email protected]: γ-aminobutyric acid (GABA) and its main receptor, the GABAA 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 GABAA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABAA 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 GABAA 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, GABAA 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 GABAA receptor gene MGPS and AD clinical features.Results: Compared with the NAD group, the AD group had a higher GABAA 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 GABAA 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 GABAA receptor MGPS and AD.Keywords: anxious depression, GABAA receptor, multi-locus genetic profile scores, dorsolateral prefrontal cortex, amygdala subregion