Brain imaging correlates of molecular genetic risk types for schizophrenia and bipolar disorder

• Applicant: Professor Dr. Axel Krug
• Subject Area: Biological Psychiatry
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 182949447

Schizophrenia is a common and severe disorder with an onset in early adulthood. Its aetiology, symptom clusters, and course are heterogeneous and are known to be under genetic control. A meta-analysis of 12 twin studies estimated heritability in liability to schizophrenia at 81%. In addition to genetic risk, there is also evidence for important gene by environment interactions contributing to overall liability. Linkage studies have identified a series of chromosomal regions that are likely to contain susceptibility genes, and highly promising association findings have been obtained for several genes in these regions (e.g. neuregulin 1 [NRG1], disrupted in schizophrenia gene 1 [DISC1], Catechol-O-methyl transferase [COMT], D-amino acid oxidase activator [DAOA also known as G72], dystrobrevin-binding protein 1 [DTNBP1] and regulator of G-protein signaling 4 [RGS4]). Among those candidates, several have also been implicated in bipolar disorder, such as NRG1, DISC1 and G72. Previous work of the investigators has found that the disorder related variants have an influence on general cognition, personality profiles, neural activation levels and brain structure in healthy individuals which is, in many cases, highly similar to the patterns found when comparing patients with schizophrenia to healthy controls. The current proposal aims at extending these results in patients. As several susceptibility genes seem to have an influence on schizophrenia as well as bipolar disorder - thus in part questioning the established strict diagnostic boundaries- it is intended to include these two diagnostic groups in these investigations in order to explore the commonalities as well as specificities of the genotype-phenotype associations across the two disorders. The phenotypes to be investigated include neuropsychological variables, personality profiles, neural activations during several cognitive and social-cognitive paradigms, whole brain and area specific morphometry as well as structural and functional connectivity. Candidate genes to be investigated will include – among others – the above mentioned variants NRG1, DISC1, G72, DTNBP1, and RGS4, but also new candidates emerging from genome-wide associations studies such as e.g. CACNA1C, ZNF804A, Neurogranin and TCF4. The aim of the proposal is to gain a deeper understanding of the pathogenetic pathways as well as the specificity of these susceptibility genes and the sensitivity of the methods employed to detect their influence in healthy subjects and patients.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Tilo Kircher; Professorin Dr. Marcella Rietschel