Catechol-O-Methyltransferaseval¹⁵⁸metGenotype Affects Processing of Emotional Stimuli in the Amygdala and Prefrontal Cortex

Abstract

Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A functional polymorphism in the COMT gene (val 158met) accounts for a fourfold variation in enzyme activity. The low-activity met 158 allele has been associated with improved working memory but with higher risk for anxiety-related behaviors. Using functional magnetic resonance imaging, we assessed the effects of COMT genotype on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 35 healthy subjects. The analysis of genotype effects was restricted to brain areas with robust activation by the task. To determine gene-dose effects, the number of met 158 alleles (0, 1, or 2) was correlated with the blood oxygen level-dependent (BOLD) response elicited by pleasant or unpleasant stimuli compared with neutral stimuli. COMT genotype had no significant impact on brain activation by pleasant stimuli but was related to the neural response to unpleasant stimuli: reactivity to unpleasant stimuli was significantly positively correlated with the number of met 158 alleles in the limbic system (left hippocampus, right amygdala, right thalamus), connected prefrontal areas (bilateral ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex), and the visuospatial attention system (bilateral fusiform gyrus, left inferior parietal lobule). Genotype explained up to 38% of interindividual variance in BOLD response elicited by unpleasant stimuli. We conclude that (1) genetic variations can account for a substantial part of interindividual variance in task-related brain activation and that (2) increased limbic and prefrontal activation elicited by unpleasant stimuli in subjects with more met 158 alleles might contribute to the observed lower emotional resilience against negative mood states.

Impact of complex genetic variation in COMT on human brain function

“…36 Within PFC, it was the right ventrolateral region that was consistently highlighted as the maximum locale for the effect of genetic variation of COMT, in good regional agreement with some previous studies. 15,41 This localization is unImpact of COMT on human brain A Meyer-Lindenberg et al likely to be due to regional variation in dopaminergic tone, since no data suggest prominent asymmetries in dopaminergic projections to human PFC. Previous work has implicated ventrolateral PFC in inhibitory control 42,43 and set shifting, 44 and a right predominance in inhibitory control has been noted.…”

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…Following the landmark study of Egan et al (2001), a range of studies have shown that the Val 158 Met allele has a small but significant impact on prefrontal cognitive performance and efficiency, with Met 158 -carrying individuals performing better and/or more efficiently than Val 158 -carrying individuals (Barnett et al, 2007b). Conversely, the Val 158 allele is associated with more 'flexible' cognitive responses (Bilder et al, 2004), especially during emotional processing (Smolka et al, 2005;Drabant et al, 2006). Apart from Val 158 Met, other common COMT SNPs are noncoding (synonymous, intronic, or in the promoter or 3 0 -untranslated regions).…”

Gene–gene effects on central processing of aversive stimuli

“…All subjects were 'Caucasians' of central European descent. Twenty-nine of these subjects have been published in previous studies, 37,38 while an additional number of subjects (n = 20) were recruited for the current study. Standardized clinical assessment with the Structured Clinical Interview I and II 40,41 was performed to exclude subjects with a lifetime history of axis I or II psychiatric disorders, according to DSM IV and ICD 10.…”

“…Interestingly, 5-HTTLPR predicted not only amygdala activity but also functional connectivity with paralimbic areas and morphometric differences in the amygdala and perigenual cingulate. 37,39 The number of low-activity COMT-Met 158 alleles was positively correlated with brain activation elicited by aversive stimuli in the left hippocampus and the right amygdala 38 and predicted opioid system activations in the amygdala and elsewhere after painful stimuli. 17 Therefore, we tested the hypothesis that processing of unpleasant stimuli in the limbic system is increased with low expression of 5-HTT, that is, higher number of S and G alleles of 5-HTTLPR and rs25531, respectively, as well as with low COMT activity, that is, the dose of met 158 alleles.…”