Catechol O-methyltransferase val¹⁵⁸met genotype and neural mechanisms related to affective arousal and regulation

Context: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val ¹⁵⁸met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. Objectives: To examine COMT val¹⁵⁸met 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.