Genetic effects on behavior are mediated by neurotransmitters and large-scale neural networks

Claims of gene-behavior associations are complex and sometimes difficult to replicate because these relationships involve many downstream endogenous and environmental processes that mediate genetic effects. Knowing these mediating processes is critical to understanding the links between genes and behavior and how these factors differ between people. We identified and characterized the effects of a gene on neurochemistry and neural networks to elucidate the mechanism, at the systems level, whereby genes influence cognition. Catechol-O-methyltransferase (COMT) degrades dopamine in the prefrontal cortex (PFC) and is polymorphic with alleles differing in enzymatic activity. We found that COMT genotype determined dopamine synthesis, such that individuals with greater COMT activity synthesized more dopamine. Dopamine synthesis in the midbrain and ventral striatum affected functional connectivity in the default mode network, likely through the mesocorticolimbic pathway, in an inverted-U pattern with greater functional connectivity in medial PFC associated with intermediate levels of COMT activity and dopamine. Greater functional connectivity correlated with greater deactivation during performance of a set-shifting task that engaged the PFC. Greater deactivation was in turn associated with better performance. The integration of these results yields a model whereby COMT affects prefrontal function by a mechanism involving dopaminergic modulation of the default mode network. The model features the well-known inverted-U function between dopamine and performance and supports the hypothesis that dopamine and the default mode network shift attentional resources to influence prefrontal cognition.