Abstract
Objective: Anxiety disorders are typically prevalent in women, but the factors contributing to sex bias are unknown. Investigations have emphasized the role of the cortico–limbic circuit including the anterior cingulate cortex (ACC) in anxiety disorders. Pregenual ACC (pgACC) was highlighted as key region for successful affect regulation, and dysregulation of transmitter balance (GABA/Glu) was
reported in anxiety disorders in this region. We therefore investigated whether a SNP in GABA synthesizing enzyme GAD65 and sex are associated with inhibitory/excitatory balance in ACC regions (pgACC and aMCC). Additionally, we explored the relationship between GAD65, sex, metabolites and harm avoidance (HA).
Methods: 107 healthy subjects (45 females, age = 27.07 ± 6.75) underwent a magnetic resonance spectroscopy in 7T. GABA and Glu levels were measured in aMCC and pgACC. Subjects completed TCI questionnaire and were genotyped for GAD65 promoter (40 G-carriers). Region by genotype by sex ANOVA was done including age as confound for GABA/Glu levels. Likewise, we tested differences for HA, and association to pgACC metabolism. Lastly, we performed an
analysis of mediating effects of GABA/Glu on GAD65 to HA,
moderated by sex.
Results: We found an interaction effect on GABA/Glu (F1,63 = 8.69, p = 0.004). Post-hoc analysis revealed that this interaction was driven by genotype difference in females in pgACC (t(37) = –2.27, p = 0.029). There was an effect of sex on HA and pgACC GABA/Glu levels (women: ρ(25) = –0.552, p = 0.003; men: ρ(31) = –0.003, p = 0.98). We also observed an effect for the moderated mediation (−1.17, −0.056).
Conclusion: Our results show that GABAergic gene polymorphisms and sex are factors contributing to anxiety endophenotypes in women via metabolic correlates in the pgACC. This interaction could be relevant for the observed sex bias in prevalence of anxiety disorders and possible sex specific treatment strategies.
