First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from Bonn, Mannheim and Basel, an international collaboration of researchers discovered two new gene regions that are connected to the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal “Nature Communications.”

Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts.

The causes of the disease are not yet fully understood, however, in addition to psychosocial triggers, genetic factors play a large role. “There is no one gene that has a significant effect on the development of bipolar disorder. Many different genes are evidently involved and these genes work together with environmental factors in a complex way,” says Prof. Sven Cichon, Director of the Department of Human Genetics at the University Hospital of Basel.

Genetic data from 24,000 people
In recent years, the scientists had already been successful in decoding several genes associated with bipolar disorder.

. In their search for further genetic risk regions, the researchers working with Prof. Markus M. Nöthen from the University of Bonn Hospital, Prof. Marcella Rietschel from the Central Institute of Mental Health of Mannheim and Prof. Sven Cichon from the University Hospital of Basel are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2,266 patients with manic-depressive disorder and 5,028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9,747 patients were compared with data from 14,278 healthy persons.

The search for genes involved in the manic-depressive disorder is like looking for a needle in a haystack. “The contributions of individual genes are so minor that they normally cannot be identified in the ‘background noise’ of genetic differences,” explains Sven Cichon, Professor for human genetics at the University of Basel. “Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically.”

Two new gene regions discovered and three known regions confirmed

Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene “ADCY2” on chromosome five and the so-called “MIR2113-POU3F2” region on chromosome six. The risk regions “ANK3”, “ODZ4” and “TRANK1” have already been described in prior studies. “These gene regions were, however, statistically better confirmed in our current,” says psychiatrist Prof. Marcella Rietschel from the Central Institute of Mental Health of Mannheim.

The researchers are particularly interested in the newly discovered gene region “ADCY2”. It codes an enzyme which is involved in the conduction of signals into nerve cells. “This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains the geneticist Prof. Markus Nöthen from Bonn. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. Their aim is to find starting points for new therapies.

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Olivia Poisson
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University of Basel