PT  - JOURNAL ARTICLE
AU  - Lejla Colic
AU  - Meng Li
AU  - Liliana Ramona Demenescu
AU  - Shija Li
AU  - Iris Müller
AU  - Anni Richter
AU  - Constanze I. Seidenbecher
AU  - Oliver Speck
AU  - Björn H. Schott
AU  - Oliver Stork
AU  - Martin Walter
TI  - GAD65 promoter polymorphism rs2236418 modulates harm avoidance in women via inhibition/excitation balance in the rostral ACC
AID  - 10.1523/JNEUROSCI.1985-17.2018
DP  - 2018 May 03
TA  - The Journal of Neuroscience
PG  - 1985-17
4099  - http://www.jneurosci.org/content/early/2018/05/03/JNEUROSCI.1985-17.2018.short
4100  - http://www.jneurosci.org/content/early/2018/05/03/JNEUROSCI.1985-17.2018.full
AB  - 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.SIGNIFICANCE STATEMENTAnxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/Glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however only in women.