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Abstract:
Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety—like traits and related neural activity in both sexes. 105 healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI), including resting state fMRI in combination with assessment of GABA and Glutamate (Glu) levels via MR spectroscopy (MRS). Regional GABA/Glu levels in ACC subregions were assessed as mediators of gene—personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC), as compared to G carriers. The pgACC drove a significant interaction of genotype, region and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated SNPs of the GABA synthesis related enzymes (GAD1, GAD2 and GLS) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated—mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women.
