Influence of COMT val158met Genotype on the Depressed Brain during Emotional Processing and Working Memory

Esther M Opmeer,Dick J Veltman,Saskia Woudstra,Mark A Van Buchem,Marie-José Van Tol,André Aleman,Nic J A Van Der Wee,Rudie Kortekaas,Brenda W Penninx,Katharina Domschke

doi:10.1371/journal.pone.0073290

Abstract

Major depressive disorder (MDD) has been associated with abnormal prefrontal-limbic interactions and altered catecholaminergic neurotransmission. The val158met polymorphism on the catechol-O-methyltransferase (COMT) gene has been shown to influence prefrontal cortex (PFC) activation during both emotional processing and working memory (WM). Although COMT-genotype is not directly associated with MDD, it may affect MDD pathology by altering PFC activation, an endophenotype associated with both COMT and MDD. 125 participants, including healthy controls (HC, n=28) and MDD patients were genotyped for the COMT val158met polymorphism and underwent functional magnetic resonance imaging (fMRI-neuroimaging) during emotion processing (viewing of emotional facial expressions) and a WM task (visuospatial planning). Within HC, we observed a positive correlation between the number of met-alleles and right inferior frontal gyrus activation during emotional processing, whereas within patients the number of met-alleles was not correlated with PFC activation. During WM a negative correlation between the number of met-alleles and middle frontal gyrus activation was present in the total sample. In addition, during emotional processing there was an effect of genotype in a cluster including the amygdala and hippocampus. These results demonstrate that COMT genotype is associated with relevant endophenotypes for MDD. In addition, presence of MDD only interacts with genotype during emotional processing and not working memory.

Highlights

Major depressive disorder (MDD) is a disorder characterized by abnormal interactions between cortical and subcortical structures [1,2] and altered catecholamine neurotransmission [3,4]
The aim of the current study was to investigate the influence of the val158met polymorphism in the gene coding for catechol-O-methyltransferase (COMT) on cortical functioning, and whether the presence of major depressive disorder (MDD) moderated these associations
We showed that during emotional processing there was an interaction between diagnosis and COMT-genotype: in healthy participants the number of met-alleles was associated with higher activation in the inferior frontal gyrus (IFG), whereas in MDD patients IFG activation was not affected by genotype

Summary

Introduction

Major depressive disorder (MDD) is a disorder characterized by abnormal interactions between cortical and subcortical structures [1,2] and altered catecholamine neurotransmission [3,4]. These disturbances affect both emotion processing [2] and executive functioning [5], and MDD is characterized by abnormal prefrontal activation during tasks tapping into these functions [2,5,6,7,8,9,10,11,12]. COMT-genotype variability has been postulated as an evolutionary switch toward a more cognitive versus a more emotional mental processing style [17]

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