Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects

Abstract

Two limiting factors of dopamine activity are the catechol-o-methyltransferase (COMT) and the dopamine transporter (DAT), which terminate dopamine activity by degradation and uptake, respectively. Genetic variants of COMT and DAT have been related to the enzymatic activity and protein availability, respectively. The Met allele of the COMT Val108/158 Met polymorphism has been associated to lower enzymatic activity and the 9-repeat allele of the DAT 40 base-pair (bp) variable number of tandem repeat (VNTR) polymorphism has been related to lower protein availability. Genotypes for COMT and DAT were determined in a sample of 75 healthy subjects, who underwent functional magnetic resonance imaging (fMRI) while performing an N-back task. To further assess the effects of the genotypes on cognition, subjects were administered the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test (CPT). Analysis of fMRI data revealed an additive effect of these two genes on brain activation in an N-back task, with subjects homozygous for the Val and the 9-repeat alleles showing the highest activation for the same level of performance. Moreover, the Val allele was related to higher number of perseverative errors on the WCST and with a higher number of commission errors on the CPT. The 10-repeat allele was associated with faster reaction times but also with a higher number of commission errors. Our results support a role of the COMT Val108/158 Met and the DAT 40 bp VNTR in both brain activation and cognition.