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

Arch Gen Psychiatry. 2006 Dec;63(12):1396-406. doi: 10.1001/archpsyc.63.12.1396.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Affect / physiology*
  • Affect / radiation effects*
  • Affective Symptoms / diagnosis
  • Affective Symptoms / genetics*
  • Amygdala / physiology
  • Arousal / genetics
  • Arousal / physiology*
  • Brain Mapping / methods
  • Catechol O-Methyltransferase / genetics*
  • Exploratory Behavior / physiology
  • Facial Expression
  • Female
  • Genotype
  • Humans
  • Limbic System / physiology*
  • Magnetic Resonance Imaging / statistics & numerical data
  • Male
  • Methionine / genetics
  • Neural Pathways / physiology
  • Oxygen / blood
  • Polymorphism, Genetic / physiology*
  • Prefrontal Cortex / physiology*
  • Synaptic Transmission / physiology
  • Temperament / physiology
  • Valine / genetics
  • Visual Perception / physiology


  • Methionine
  • Catechol O-Methyltransferase
  • Valine
  • Oxygen