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Gene–gene effects on central processing of aversive stimuli

Molecular Psychiatry volume 12, pages 307–317 (2007)Cite this article

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.

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (He 2597/7-3, Sm 80/1-1 & SFB 636/C1) and the German Ministry of Education and Research (NGFN-2 No. 01 GS 0475, Baden-Württemberg Consortium for Addiction Research No. 01 EB 0110/0410).

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Authors and Affiliations

  1. Department of Psychiatry, Technische Universität Dresden, Dresden, Germany

    M N Smolka

  2. Central Institute of Mental Health, Mannheim, Germany

    M N Smolka, M Bühler, G Schumann, S Klein, M Moayer, A Zimmer, J Wrase, H Flor, K Mann & A Heinz

  3. Graduate School of Neural and Behavioural Sciences, University of Tübingen, Tübingen, Germany

    M Bühler

  4. King's College London, Section of Addiction Biology, Institute of Psychiatry, London, UK

    G Schumann

  5. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA

    X-Z Hu & D Goldman

  6. Department of Psychiatry of the Charité, Charité Campus Mitte, Berlin, Germany

    J Wrase & A Heinz

  7. Department of Psychiatry, University of Hamburg, Hamburg, Germany

    D F Braus

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  1. M N Smolka
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Smolka, M., Bühler, M., Schumann, G. et al. Gene–gene effects on central processing of aversive stimuli. Mol Psychiatry 12, 307–317 (2007). https://doi.org/10.1038/sj.mp.4001946

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