Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain

Abstract

Functional polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) genes modulate dopamine inactivation, which is crucial for determining neuronal signal-to-noise ratios in prefrontal cortex during working memory. We show that the COMT Met158 allele and the DAT 3' variable number of tandem repeat 10-repeat allele are independently associated in healthy humans with more focused neuronal activity (as measured with blood oxygen level-dependent functional magnetic resonance imaging) in the working memory cortical network, including the prefrontal cortex. Moreover, subjects homozygous for the COMT Met allele and the DAT 10-repeat allele have the most focused response, whereas the COMT Val and the DAT 9-repeat alleles have the least. These results demonstrate additive genetic effects of genes regulating dopamine signaling on specific neuronal networks subserving working memory.

Figure 1.

Working memory behavioral results. Performance accuracy results for the 2-Back task across genotype groups. Performance is represented as mean percentage of correct responses (±SEM).

Figure 2.

Genotype-based analyses of the working memory BOLD fMRI response. First row, The effect of COMT with Met homozygous subjects having the most focused engagement of areas in BA 6, 9, and 24. Second row, The effect of DAT with 10-repeat homozygous subjects having the most focused engagement of areas in BA 9, 8, and 24. Third row, The combined effect of COMT and DAT with COMT Met homozygous and DAT 10-repeat homozygous subjects having the most focused engagement of areas in BA 6, 9, and 24. Means ± 0.95 SE plots (4th row) showing percentage of signal change from BA 24 (left) and BA 9 (right) from the latter analyses in all eight genotype groups. These graphs suggest the additive effect of the two genotypes on percentage signal change.