53 While

these are therefore not monocausally related to schizophrenia, they are one of the best genetic clues yet for a genetical high-risk state that deserves intensive further study. This applies both to chartacterizing brain phenotypes in subjects carrying or not carrying the disorder, and to trying to further dissect why these, and not any of the many other microdeletions present in the human Inhibitors,research,lifescience,medical population, increase risk for psychosis. For the former approach, the main problem is that due to the relative rarity of these variants even in clinical populations, large numbers will have to be screened and characterized. Nevertheless, this work is ongoing and promises insights not only in studying the phenotypes of each of these variants by itself, but also in examining whether there are overlaps in structural or neurofunctional impairments across these microdeletions that would identify core systems related to a high-risk state. For the latter Inhibitors,research,lifescience,medical attempt of trying to understand why these specific

microdeletions are highrisk, complex cis- and trans-acting genetic effects (ie, those that concern the genes affected by the microdeletion itself, or outside of it) will have to be considered. However, a simple hypothesis that can be tested is Inhibitors,research,lifescience,medical whether there could be, by chance, several common risk variants for schizophrenia located in spatial proximity that are jointly affected by a microdeletion, causing a superadditive effect. Some preliminary evidence for this idea comes from 22q11DS, which includes the muchstudied risk gene COMT, discussed above, but also several other genes where schizophrenia Inhibitors,research,lifescience,medical risk variants have been studied. One of these, PRODH, encoding proline oxidase (POX), has been associated with schizophrenia Inhibitors,research,lifescience,medical through linkage and association. A recent study showed that functional

JAK inhibitor review polymorphisms had opposite effects on schizophrenia risk depending on whether they increased or decreased POX activity54 In multimodal genetic imaging, both functional (working memory and emotional recognition) and structural (VBM) datasets showed dissociable genetic effects: risk haplotype carriers had decreased striatal volume and these increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity, mirroring findings in patients and suggesting that functional genetic variation in POX impacts on neostriatal-frontal circuits mediating risk and protection for schizophrenia. Since, as reviewed above, the biochemically unrelated COMT gene on overlapping circuitry in human brain, this suggests a neural mechanism whereby deletion of both genes in 22q11 syndrome could have a superadditive impact on schizophrenia risk.