The idea that Val dose might influence cortical maturation in HCs by directly modifying dopaminergic influences on neurogenesis and neuronal differentiation provides a parsimonious account for how the disrupted gene–brain relationships we observe in COS probands and SIB groups could arise. For example, many dopaminergic influences on cortical development are D1-mediated (Bhide, 2009), and both patients with schizophrenia and their healthy monozygotic co-twins show increased cortical D1 density compared to HCs (Hirvonen et al., 2006). These D1 abnormalities are hypothesized to be a response to cortical hypodopaminergia, and are more severe in affected probands compared to unaffected relatives (Hirvonen et al., 2006). Thus, heritable abnormalities of DA signaling shared by COS probands and SIBs could disrupt the relationship between Val dose and cortical development in both groups compared to HCs. Under this model, more atypical cortical DA signaling in affected probands relative to their healthy relatives could account for our finding that the higher-functioning Val allele is associated with more persistent CT deficits in COS probands than in unaffected SIBs. Although highly speculative, this proposal has implications for the two
