1. ¹Department of Psychiatry, Technische Universität Dresden, Dresden, Germany
2. ²Central Institute of Mental Health, Mannheim, Germany
3. ³Graduate School of Neural and Behavioural Sciences, University of Tübingen, Tübingen, Germany
4. ⁴King's College London, Section of Addiction Biology, Institute of Psychiatry, London, UK
5. ⁵Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
6. ⁶Department of Psychiatry of the Charité, Charité Campus Mitte, Berlin, Germany
7. ⁷Department of Psychiatry, University of Hamburg, Hamburg, Germany

Correspondence: Dr A Heinz, Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Charité – Universitätsmedizin Berlin, Schumannstr. 20-21, 10117 Berlin, Germany. E-mail: andreas.heinz@charite.de

Received 17 April 2006; Revised 30 October 2006; Accepted 6 November 2006; Published online 9 January 2007.

Abstract

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene–gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val¹⁵⁸Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val¹⁵⁸Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met¹⁵⁸ alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.