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The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives

Published online by Cambridge University Press:  29 July 2010

G. Lelli-Chiesa
Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London, UK Department of Psychiatry, Sant'Andrea Hospital, Second Medical School, La Sapienza University, Rome, Italy
M. J. Kempton
Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London, UK
J. Jogia
Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London, UK
R. Tatarelli
Department of Psychiatry, Sant'Andrea Hospital, Second Medical School, La Sapienza University, Rome, Italy
P. Girardi
Department of Psychiatry, Sant'Andrea Hospital, Second Medical School, La Sapienza University, Rome, Italy
J. Powell
MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, London, UK
D. A. Collier
Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK
S. Frangou*
Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London, UK
*Address for correspondence: Dr S. Frangou, Section of Neurobiology of Psychosis (PO66), Department of Psychosis Studies, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK. (Email:



The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala–prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action.


We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls.


Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls.


Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.

Original Articles
Copyright © Cambridge University Press 2010

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