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
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