22 Other dopaminergic risk genes Three risk single nucleotide polymorphisms (SNPs) in the gene for the dopamine D2 receptor, DRD2, showed opposite effects in SB431542 patients and controls during a working memory task:

enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients,29 presumably because patients and controls are positioned on opposite Inhibitors,research,lifescience,medical sides of the inverted-u-shaped curve governing the relationship of dopaminergic simulation and prefrontal activity. On the postsynaptic side, Regulator of Gprotein signaling 4 (RGS4) modulates dopamine signal transduction by affecting G alpha-GTP binding. Allelic variation in RGS4 by itself modulated frontoparietal and frontotemporal activation

during working memory and was associated with frontal gray and white matter Inhibitors,research,lifescience,medical structural volume reductions.30 Further into the postsynapse, the pivotal integrator of information in dopaminoceptive neurons for the so-called canonical signal transduction pathway is dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by the gene PPP1R1B. A frequent PPP1R1B haplotype related to risk for schizophrenia predicted reduced striatal volume and activation Inhibitors,research,lifescience,medical (in good agreement with the expression profile of DARPP-32) and increased structural and functional connectivity of striatum with lateral prefrontal cortex in a large sample of genotyped healthy controls.31 Interestingly, genetic variation in AKT1, encoding another key signal transduction pivot, but now

for the non-canonical, beta-arrestin mediated dopaminergic pathway, Inhibitors,research,lifescience,medical similarly predicted reduced frontostriatal volume as well as inefficient prefrontal activation during working memory.32 Taken together, these two studies provide strong support for the prefrontoneostriatal system as a core circuit for dopaminergic variation related Inhibitors,research,lifescience,medical to schizophrenia risk. Investigating a panel of dopamine-related genes during a reward task,33 polymorphisms in DRD2 (141C deletion), DAT1 (9-repeat) and DRD4 (7-repeat), were related to ventral striatal activity, while COMT rs4680 was not, in agreement with its predominant role in prefrontal cortex activity. Genome-wide significant variants Despite their clear Cediranib (AZD2171) and often convergent impact on imaging phenotypes, the usefulness of candidate genes for understanding schizophrenia is debated because these a-priori hypothesized variants often show an inconsistent effect on the categorical disease phenotype itself. Genome -wide association studies (GWAS) offer an alternative, hypothesis-free way to identify genetic variants associated with the disease. While it is in our view unlikely that GWAS will provide all answers about common genetic variants impacting on schizophrenia, any variant that does survive the extreme amount of statistical thresholding that this method requires certainly merits study using intermediate imaging phenotypes.