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Role of genetic interaction between COMT and Dysbindin in cognitive and schizophrenia-related abnormalities

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Investigating mental ill health genes

Scientists carried out an in-depth investigation into two potential schizophrenia susceptibility genes. They successfully identified key mechanisms contributing to schizophrenia, a debilitating and costly psychiatric disorder.

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To provide mechanistic insights into cognitive abnormalities and schizophrenia-related phenotypes, European researchers built on earlier related work through the EU-funded SCHIZOGENES (Role of genetic interaction between COMT and Dysbindin in cognitive and schizophrenia-related abnormalities) project. The team developed a suite of innovative tasks with high translational validity for human studies. They probed the effects of memory load and environmental changes and automatically dissected different aspects of attentional control in mice. A machine-learning-based system was able to finely analyse social cognition and behaviours, which are key altered features in human patients affected by schizophrenia. Under examination were the two susceptibility genes, catechol-O-methyltransferase (COMT) and dysbindin (dys). In schizophrenia, the dys-1 gene acts as a bridge between the changes in the dopaminergic and glutamatergic systems. Interestingly, COMT and dys genes interact and a reduction in expression in any one of them produces memory advantages. Cutting expression in both genes however yields memory deficits. Modification of COMT can modulate attention, impulsivity, stress reactivity, compulsivity, flexibility and motivation, depending on gender and different environmental factors. Genetic reduction of COMT transcription improved selective attention switching between different perceptual dimensions but impaired serial reversal learning. Researchers were also able to predict genetic-driven phenotypes in humans using mouse models. The reduction in COMT enzyme was accompanied by a thickening of the prefrontal cortex (PFC) of healthy human males but not females. Gender also influenced genotype effects in cognitive functions like working memory. Moreover, COMT-dys gene interaction affected PFC-related behaviours in humans. Dissemination of SCHIZOGENES results includes publications, lectures, poster presentations at national and international meetings, and securing grants for further work. Presentation of scientific discoveries at national and international meetings has enabled knowledge sharing with other European laboratories. Project work has thereby contributed to the European Research Area and boosted the transfer of resources and knowledge slated to benefit neurophysiological research. SCHIZOGENES data has contributed to a knowledge platform on specific genetic mechanisms that contribute to psychiatric states such as schizophrenia. Identification of groups of humans with the relevant genetic profiles as indicated in the study will direct research for more effective therapeutic strategies.


Psychiatric, schizophrenia, gene, cognitive abnormalities, COMT, Dysbindin

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