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The Capital Region of Denmark - a part of Copenhagen University Hospital

High resolution mapping of functional brain networks perturbed by genetics in psychiatric diseases

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In the last 15 years the genomic revolution has enabled analyzing the genetics of many common human diseases including metabolic, psychiatric, and immunological disorders. Particularly in schizophrenia these efforts have been very successful as exemplified by a recent landmark study that revealed more than a hundred genomic regions reproducibly associated to the disease. While this study serves as a strong starting point for understanding the biology of schizophrenia it has been much more challenging than anticipated to translate robust genetic findings into an actionable understanding of the disease processes - a challenge primarily due to our very limited understanding of the molecular biology and neurophysiology of the human brain. This is currently a key bottleneck towards scientific progress and therapeutic intervention.

We propose to overcome these challenges through an integrative approach that leverages recent genetic studies with large-scale proteomics experiments to systematically derive human brain pathways (of physically interacting proteins) perturbed in patients with schizophrenia. Our approach exploits transformative new technology and data that has just become mature: (a) We will capitalize on unbiased genetic data in schizophrenia to choose corresponding proteins as the starting point of the proteomic pathway analysis. (b) We will exploit new experimental proteomics technology to map the pathways of these proteins at high resolution. (c) The proteomics experiments will be executed in human neurons generated at scale from induced pluripotent stem cells - a newly developed methodology. Overall, our approach will create a resource of experimentally derived pathways in the human brain relevant to schizophrenia. We will exemplify how this resource enables targeted and cost-efficient analyses of the biology underlying disease, the discovery of new genetic risk factors, as well as clinical stratification of patients based on genetic data.

    Research areas

  • Health Sciences - Schizophrenia Spectrum and Other Psychotic Disorders, Epidemiologic, Genetic Techniques, Registerbased research

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