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Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis

Molecular Psychiatry volume 15, pages 918–927 (2010)Cite this article

Abstract

Genetic variation in catechol-O-methyltransferase (COMT), encoding an enzyme critical for prefrontal dopamine flux, has been studied extensively using both behavioral and neuroimaging methods. In behavior, pleiotropic action of a functional Val158Met (rs4680) polymorphism on executive cognition and emotional stability has been described and proposed to be of evolutionary significance (the ‘warrior/worrier’ hypothesis). We conducted a meta-analysis of all available neuroimaging studies of rs4680 to investigate the evidence for a neural substrate of this behavioral pleiotropy. We show significant association between the COMT genotype and prefrontal activation, with large (d=0.73) effect size without evidence for publication bias. Strong and opposing effects were found for executive cognition paradigms (favoring Met allele carriers) and emotional paradigms (favoring Val), providing meta-analytical evidence for a neural substrate for the pleiotropic behavioral effects of COMT genetic variation and validating the use of intermediate phenotypes as a method to bridge between genes and behavior.

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Acknowledgements

The funding for this study was provided by BMBF (NGFNplus MooDS) and DFG (SFB 636-B7).

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  1. Department For Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany

    D Mier, P Kirsch & A Meyer-Lindenberg

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Correspondence to A Meyer-Lindenberg.

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Mier, D., Kirsch, P. & Meyer-Lindenberg, A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 15, 918–927 (2010). https://doi.org/10.1038/mp.2009.36

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