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

Mol Psychiatry. 2010 Sep;15(9):918-27. doi: 10.1038/mp.2009.36. Epub 2009 May 5.


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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Catechol O-Methyltransferase