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Emily M. Drabant, BA; Ahmad R. Hariri, PhD; Andreas Meyer-Lindenberg, MD, PhD; Karen E. Munoz, BA; Venkata S. Mattay, MD; Bhaskar S. Kolachana, PhD; Michael F. Egan, MD; Daniel R. Weinberger, MD

Arch Gen Psychiatry. 2006;63:1396-1406.

Context  Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val¹⁵⁸met) 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.

Author Affiliations: Genes, Cognition, and Psychosis Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md. Dr Hariri is now with the Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pa.

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