Psychological Medicine

Original Articles

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

G. Lelli-Chiesaa1a2, M. J. Kemptona1, J. Jogiaa1, R. Tatarellia2, P. Girardia2, J. Powella3, D. A. Colliera4 and S. Frangoua1 c1

a1 Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London, UK

a2 Department of Psychiatry, Sant'Andrea Hospital, Second Medical School, La Sapienza University, Rome, Italy

a3 MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, London, UK

a4 Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK


Background 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.

Method 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.

Results 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.

Conclusions 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.

(Received November 04 2009)

(Revised May 30 2010)

(Accepted June 26 2010)

(Online publication July 29 2010)


c1 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: