Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation |
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Authors: | Drabant Emily M Hariri Ahmad R Meyer-Lindenberg Andreas Munoz Karen E Mattay Venkata S Kolachana Bhaskar S Egan Michael F Weinberger Daniel R |
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Affiliation: | Genes, Cognition, and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health/DHHS, 10 Center Drive, Bethesda, MD 20892, USA. |
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Abstract: | CONTEXT: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking. DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes. RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility. CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals. |
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