Regardless of study design, use of in-vivo neuroimaging means that the proximal cellular and molecular mechanisms underlying observed relationships between Val158Met genotype and cortical development remain to be determined. However, the factors driving any observed genetic association exist on a theoretical spectrum that extends between two extremes—total environmental mediation and total independence from environmental influences. Existing studies of the COMT Val158Met variant argue for a mixed model. For example, the possibility of environmental mediation is raised by a recent report that Val dose in HCs is associated with an increased tendency to respond to uncertainty in an exploratory (“trying a new tack to see what happens”) rather than exploitative (“sticking to what you know”) fashion (Frank et al., 2009). These genotype-related differences in behavioral style could result in the accrual of greater experiential diversity across the lifespan, with consequences for cortical development (Bennett et al., 1969). On the other hand, variation in DA signaling arising from allelic differences at Val158Met is also likely to have direct consequences for basic DA-sensitive cellular processes that are fundamental to neurogenesis and neuronal and inter-neuron differentiation (Bhide, 2009).
