GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC
Autor: | Iris Müller, Lejla Colic, Constanze I. Seidenbecher, Meng Li, Oliver Speck, Martin Walter, Liliana Ramona Demenescu, S. Li, Björn H. Schott, Gusalija Behnisch, Anni Richter, Oliver Stork |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Genotype genetics [Polymorphism Genetic] Gyrus Cinguli Polymorphism Single Nucleotide GAD1 GAD2 03 medical and health sciences Young Adult 0302 clinical medicine Neurochemical Internal medicine medicine Avoidance Learning genetics [Glutamate Decarboxylase] Humans ddc:610 Promoter Regions Genetic Anterior cingulate cortex Research Articles glutamate decarboxylase 2 Brain Mapping Polymorphism Genetic business.industry Glutamate Decarboxylase General Neuroscience Glutamate receptor physiology [Gyrus Cinguli] medicine.disease physiology [Avoidance Learning] Magnetic Resonance Imaging 030104 developmental biology medicine.anatomical_structure Endocrinology Endophenotype Harm avoidance Anxiety Female medicine.symptom business 030217 neurology & neurosurgery Personality |
Zdroj: | The journal of neuroscience 38(22), 5067-5077 (2018). doi:10.1523/JNEUROSCI.1985-17.2018 Journal of Neuroscience |
Popis: | 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 inGAD2gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (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 lowerGAD2promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with 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 single nucleotide polymorphisms of the GABA synthesis related enzymes (GAD1,GAD2, andGLS) 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 theGAD2gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. TheGAD2gene 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. |
Databáze: | OpenAIRE |
Externí odkaz: |