We then move on to the emerging field for variants with genome-wide association support. In conclusion, we discuss areas of merit for further study in imaging genetics of schizophrenia, both from the genetics and neural systems-level perspective: epistasis and structural variations in the human genome. COMT Starting with the classic 2001 study by Egan and coworkers,6 the catechol-0-methyltransferase (COMT) gene, COMT, has been by far the most-studied gene in the schizophrenia imaging genetics literature. COMT degrades catecholamines, including dopamine (DA).7,8 The

COMT gene consists of two promoters and six exons which encode both the membrane-bound Inhibitors,research,lifescience,medical (MB-COMT) and soluble (S-COMT) forms of COMT

and is located on chromosome 22q11.22-23. This region is implicated in schizophrenia by linkage studies,9 as well as in 22q11.2 deletion syndrome, Inhibitors,research,lifescience,medical which is associated with strongly increased risk for psychosis.10 Of the two confirmed isoforms, MBCOMT is predominantly expressed in the central nervous system at neuronal dendritic processes throughout the cortex, cerebellum, amygdala, putamen, thalamus, spinal cord, and hippocampus.11,12 Postmortem Dorsomorphin purchase studies have shown that COMT is particularly concentrated Inhibitors,research,lifescience,medical in the extrasynaptic spaces of the prefrontal cortex and hippocampus.13 Since prefrontal dopamine transporters are scarce, COMT is thought to play a key role in clearing dopamine in the prefrontal cortex.14 An evolutionarily recent Inhibitors,research,lifescience,medical functional single nucleotide polymorphism (SNP) in COMT results in the amino acid substitution of valine (val) with methionine (met) at codon 158 of MB-COMT (rs4680,

GenBand accession no. “type”:”entrez-nucleotide”,”attrs”:”text”:”Z26491″,”term_id”:”403303″,”term_text”:”Z26491″Z26491, Inhibitors,research,lifescience,medical Savitz et al 2005). This substitution leads to a significant (38%) decrease in enzymatic activity in the brain and lymphocytes15 of the polypeptide containing the met allele compared with the val allele. Consequently, met carriers have a higher level of prefrontal extracellular dopamine.16,17 A large body of work has demonstrated an impact of this genetic variant on cognitive and affective processing. The literature on the functional aspects of the common rs4680 val/met polymorphism ALOX15 in COMT has been recently reviewed.5 In a meta-analysis of all available functional neuroimaging studies of rs4680 up to the end of 2008 (which are consequently not covered again in the present review), a significant association between the COMT genotype and prefrontal activation was found. The effect size was large (d=0.73) without evidence for publication bias. In the next step, studies were subdivided into studies relating to executive cognition paradigms and those that were related to emotional processing.