The lack of association of rs279858 with the expression of chr4p12 GABAA genes in adult post-mortem brain suggests that genetic variation in this region may increase risk for substance-related disease via developmental mechanisms. However, more research is needed to show a developmental influence of chr4p12 variation in vivo. Evidence of genetic variation influencing development but contributing to disease risk in adulthood has been described for the serotonin transporter-linked polymorphic region, 5-HTTLPR of SLC6A4. Carriers of the 5-HTTLPR S-allele are more susceptible to anxiety and depression (Caspi et al., 2010), have reduced functional and white matter connectivity of the amygdala and anterior cingulate cortex (Pacheco et al., 2009, Pezawas et al., 2005) and show enhanced amygdala activation to fear stimuli (reviewed in (Munafo et al., 2008). In rodents, anxiety- and depression-like behavior in adult mice were only seen when the serotonin transporter was disrupted early in development (Ansorge et al., 2004), suggesting a developmental effect of SLC6A4 genotype on susceptibility to anxiety, depression, and regional brain connectivity in adulthood.
