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


OBJECTIVE
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.


METHODS
Within-subject functional magnetic resonance imaging study.


METHODS
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.
Drabant
Emily M
EM
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.
Hariri
Ahmad R
AR
Meyer-Lindenberg
Andreas
A
Munoz
Karen E
KE
Mattay
Venkata S
VS
Kolachana
Bhaskar S
BS
Egan
Michael F
MF
Weinberger
Daniel R
DR
D000328:Adult; D000339:Affect / Q000502:physiology* / Q000528:radiation effects*; D000342:Affective Symptoms / Q000175:diagnosis / Q000235:genetics*; D000679:Amygdala / Q000502:physiology; D001143:Arousal / Q000235:genetics / Q000502:physiology*; D001931:Brain Mapping / Q000379:methods; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology; D005149:Facial Expression; D005260:Female; D005838:Genotype; D006801:Humans; D008032:Limbic System / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data; D008297:Male; D008715:Methionine / Q000235:genetics; D009434:Neural Pathways / Q000502:physiology; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D013694:Temperament / Q000502:physiology; D014633:Valine / Q000235:genetics; D014796:Visual Perception / Q000502:physiology
D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen