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

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 Met(158) 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 DAT10-repeat allele have the most focused response, whereas the COMTVal and the DAT9-repeat alleles have the least. These results demonstrate additive genetic effects of genes regulating dopamine signaling on specific neuronal networks subserving working memory.