Imaging Genetics: Neurale Mechanismen des genetischen Riskos für Schizophrenie und affektive Störungen

Coordinator:       Prof. Dr. med. Dipl. Math. Andreas Meyer-Lindenberg
Institution:         Zentralinstitut für Seelische Gesundheit Mannheim   

Genetic risk variants for psychiatric disorders impact onto behavioural phenotypes such as disease status, treatment response and social adaptation only indirectly, through an effect on brain function. Neuroimaging has proven highly sensitive for characterizing neural systems-level structural and functional alterations associated with common allelic variation, leading to the discovery of neural mechanisms of genetic risk that refine the biological definition of the psychoses. At the same time, higher penetrance and simpler genetic architecture on the intermediate phenotype level also contributes to gene identification in a forwards genetic approach. In the context of  NGFNplus, the neuroimaging project pursues two specific research goals: First the investigation of the effect of risk variants for affective and schizophrenic disorders on brain structure and function (a reverse genetics, bottom-up, gene-driven approach) and second the investigation of shared and distinct mechanisms related to genetic risk for these disorders (a topdown, neural systems driven approach).
The research goals of the project are supported by the establishment of a validated, reliable battery of neuroimaging structural and functional assessment sensitive to genetic variation that access major systems of executive cognitive control, memory, emotional regulation, reward processing and social cognition associated with affective and schizophrenic disorders. The participating imaging centres will each scan relatives of patients and matched controls over the duration of the project to reach a sample size of at least 200 controls and 100 siblings in each category for neuroimaging genetics. The main hypotheses of the project are that multimodal neuroimaging will identify neural mechanisms significantly linked to genetic risk for the disorders under study, that domain-specific neural processing abnormalities across diagnostic boundaries will map onto genetic associations with several traditional diagnostic categories, specifying both shared and distinct neurobiological mechanisms across the spectrum of psychotic and mood disorders and finally that shared and distinct neural mechanisms associated with disease risk conferred by single genes will map on differences in brain structure and function in relatives of patients, vs. controls, establishing them as heritable intermediate phenotypes. Those phenotypes will be of great value for the identification and monitoring of new treatment target.
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