Cognitive effects of genetic variation in monoamine neurotransmitter systems: a population-based study of COMT, MAOA, and 5HTTLPR

Abstract

Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well-characterized common functional polymorphisms in the genes MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition.

FIG 1

Schematic diagram of major routes of inactivation of the monoamine neurotransmitters serotonin, dopamine, and NA in prefrontal cortical synapses. The enzyme monoamine oxidase, located in the mitochondrial cell wall degrades 5-HT, DA, and NA into the compounds 5HIAA, DOPAC, and DHMA. A second enzyme, catechol-O-methyltransferase (COMT) degrades dopamine and, to a lesser extent, NA, forming the products 3-methoxytyramine (3-MT) and normetanephrine. Transporter proteins located in the cell membrane allow reuptake of serotonin and NA into the presynaptic neuron, but dopamine transporters are predominantly located extrasynaptically in primate prefrontal cortex [Lewis et al., [, increasing the importance of enzymatic degradation of DA.

FIG 2

Working memory global score (mean, SE) by COMT and MAOA genotype in 2,324 boys at age 10 years. COMT × MAOA interaction term: F = 4.17; DF 2,2324, P = 0.016.