Catechol-o-methyltransferase has been intensely investigated in schizophrenia genetics as a functional candidate gene because of its active role in DA metabolism (Weinshilboum et al., 1999), and as a structural candidate gene because it sits within a chromosome 22q11 deletion that results in velocardiofacial syndrome (VCFS); a neurogenetic disorder that shows 30-fold increased risk for schizophrenia-like psychosis (Murphy, 2002). The catabolic action of COMT is particularly important in regulating DA levels in the pre-frontal cortex (PFC) (Lewis et al., 2001). The Val158Met SNP within COMT (rs4680) encodes a Valine→Methionine substitution at protein residue 158 of the membrane-bound COMT isoform that predominates in brain tissue. This substitution impacts COMT protein thermostability, such that the Val allele encodes a protein with approximately 40% greater enzymatic activity than the Met allele, as demonstrated in lymphocytes as well as postmortem human dorsolateral prefrontal cortex (dlPFC) tissue (Chen et al., 2004). Increased DA catabolism imparted by the Val allele is thought to result in reduced synaptic DA availability, with consequences for PFC function that vary according to background dopaminergic tone (Tunbridge et al., 2006). Thus, comparing
