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

      Molecular Psychiatry

      Catechol O-Methyltransferase, genetics, Genetic Pleiotropy, physiology, Genetic Variation, Humans, Magnetic Resonance Imaging, Prefrontal Cortex, anatomy & histology

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          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 Val(158)Met (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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          Journal
          19417742
          10.1038/mp.2009.36

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