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Gene variant responsible for defective communication in the brain

Schizophrenia and bipolar disorder are psychological diseases that are both common and severe. The causes of these diseases are largely unknown. It has been known for some time that certain hereditary factors enhance the risk of developing schizophrenia or a manic-depressive disorder. Researchers from the ZI in Mannheim and the Department of Medicine (Psychology) at the University of Bonn have managed to identify the effects of such gene variants on brain function. In healthy carriers of this gene variant, the cooperation between the brain areas that are involved in working memory, attention control and emotion processing is defective. This is the first time a mechanism has been identified which genes use to mediate the risk of developing such diseases.

Brain areas (in colour) whose links are defective in healthy carriers of a risk gene variant for schizophrenia and bipolar disorder. © Esslinger et al., Science 2009

Healthy carriers of a common gene variant that enhances the risk of developing schizophrenia and bipolar disorder, reveal symptoms of defective intercooperation of brain areas mainly involved in working memory, attention control and emotion processing. This finding was published by Christine Esslinger, Andreas Meyer-Lindenberg and Peter Kirsch from the Central Institute of Mental Health, University of Heidelberg/Medical Faculty in Mannheim along with Henrik Walter from the Department of Medical Psychology at the Hospital for Psychiatry and Psychotherapy at the University of Bonn in the scientific journal SCIENCE (issue published 1st May 2009). The researchers provided evidence of a mechanism through which genes mediate the risk of contracting these severe diseases - a discovery that may also open up new strategies for therapy research in this area.

Schizophrenia and bipolar disorder (manic-depressive disorder) are common, severe and often also chronic psychiatric syndromes. Although their causes are still largely unknown, it is known that hereditary factors (gene variants) carry the lion's share of the risk of contracting one or other of the diseases. Last year, an international group of researchers was able to identify a variant of the ZNF804A gene that is, with a high level of certainty, very possibly associated with the risk of contracting either of the diseases.

Carriers of the high-risk gene variant exhibit structures that are strongly linked with the right prefrontal cortex © Esslinger et al., Science 2009


In a project funded by the German Ministry of Education and Research under the National Genome Research Network (NGFNplus) and initiated by Andreas Meyer-Lindenberg from the Central Institute of Mental Health, the researchers in Mannheim (led by Peter Kirsch and Marcella Rietschel) and Bonn (led by Henrik Walter and Sven Cichon) succeeded in identifying the effects of this gene variant on brain function. The scientists examined 115 healthy people using functional magnetic resonance imaging (fMRI). Carriers of the high-risk gene variant exhibited a change in the communication between the dorsolateral prefrontal cortex (DLPFC), an area that is important for working memory and higher brain functions, with other regions of their brains: While the communication between the right and left DLPFC had become impaired in carriers of the high-risk gene, the link (see picture) between the DLPFC and the hippocampus, another brain area that is important for memory, improved. Both these abnormalities had already been shown to exist in patients suffering from schizophrenia. The researchers also found that carriers of this high-risk gene also displayed an enhanced linkage between the amygdala, a structure that plays an active role in the way in which we cope with our emotions, and a number of other cerebral regions. The researchers have related this phenomenon to bipolar impairment as it is characterised by erratic mood swings.

Over 100 years ago, the German psychiatrist Carl Wernicke assumed that schizophrenia is the result of defective cooperation between areas of the brain. The new study confirms this assumption by combining modern genetics, brain imaging and molecular factors. The function of the protein encoded by the gene ZNF804A is still not clear but is currently being investigated as a potential starting point for new forms of therapy. "It is very impressive that modern imaging methods are able to visualise such subtle genetic effects in the living brain," said Professor Peter Kirsch, head of the Brain Imaging group at the ZI. "The gene variant only contributes to a small extent to such disorders," said Dr. Christine Esslinger (ZI).

The study also involved Leila Haddad, Daniela Mier, Kyeon Raab and Stefanie Witt (all from the ZI) as well as Claudia Arnold, Susanne Erk, Knut Schnell and Carola Opitz von Boberfeld (all from the University of Bonn). The study also received funds from the DFG (SFB 636-B7, University of Heidelberg).

Press release - Central Institute of Mental Health (ZI) Mannheim
30.04.2009 Sigrid Wolff, Public Relations

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/gene-variant-responsible-for-defective-communication-in-the-brain