Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis.
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.
Mier
D
D
Department For Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany.
Kirsch
P
P
Meyer-Lindenberg
A
A
D002394:Catechol O-Methyltransferase / Q000235:genetics*; D058685:Genetic Pleiotropy / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D008279:Magnetic Resonance Imaging; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000502:physiology*
D002394:Catechol O-Methyltransferase