16. May 2021

Largest genetic study to date on bipolar disorder Largest genetic study to date on bipolar disorder

In cooperation with the University of Bonn, researchers studied a total of 400,000 people

Genetic factors contribute significantly to the development of bipolar disorder. The probably largest analysis to date on the hereditary factors involved has now been published. More than 40,000 affected individuals and 370,000 controls were included in the study; some 320 researchers around the globe were involved. Lead partners for the project included the Icahn School of Medicine, New York, the University of Oslo and the University Hospital Bonn. The results not only provide new insights into the genetic basis of the disease, but also into possible risk factors in living conditions or behavior. They are published in the journal "Nature Genetics".

Prof. Dr. Markus M. Nöthen (left)
Prof. Dr. Markus M. Nöthen (left) - and Jun.-Prof. Dr. Andreas Forstner (right) from the Institute of Human Genetics at the University Hospital Bonn. © Andreas Stein/UKB
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The name "bipolar disorder" is not a coincidence: The mood of those affected oscillates between two extremes. Sometimes they are so depressed for weeks that they barely manage to go about their daily activities. At other times, there are phases when they feel euphoric and full of energy, frantically pursuing their projects. The term "manic depression" has therefore become established in everyday language. Around one percent of all people develop the disease in the course of their lives. Their suffering is immense.

Risk factors include early childhood traumas such as abuse or the loss of a parent, but also, for example, a stressful lifestyle or the use of certain drugs. To a large extent, however, bipolar disorder is a matter of genes: Experts estimate the contribution of genetic makeup at 60 to 85 percent. Hundreds of genes are probably involved. "However, we only know a small part of them so far," explains Jun.-Prof. Dr. Andreas Forstner. The researcher, who recently moved from the University of Marburg to a junior professorship at the Institute of Human Genetics at the University of Bonn and the Institute of Neuroscience and Medicine (INM-1) at Forschungszentrum Jülich, is one of the lead authors of the current study.

DNA lexicon compared at hundreds of thousands of sites

This greatly improves the understanding of the genetic basis. The international consortium searched the DNA of more than 400,000 participants for abnormalities. Each individual's genetic blueprint is like a giant lexicon with around three billion letters. The content of this DNA lexicon differs from person to person. However, for people with bipolar disorder, at least the passages that relate somewhat to the disorder should be similar. And the researchers took advantage of this basic assumption: By comparing the DNA of their subjects at many hundreds of thousands of sites that occur variably in the population, they were able to identify genetic regions that are thought to contribute to the disease.

"In this way, we identified 64 gene loci associated with bipolar disorder," explains Prof. Dr. Markus Nöthen, head of the Institute of Human Genetics. "33 of them were previously unknown." The hits thus also provide clues to new therapeutic approaches. For example, the genes located in the identified regions often contain building instructions for so-called ion channels. These are essential for generating electrical pulses in the brain, the action potentials. The study draws particular attention to calcium channels. "They seem to be involved in the development of the disease," Forstner explains. "There are drugs that affect the function of these channels, but so far they have only been approved for the treatment of other diseases. Maybe they could also be an option for bipolar disorder therapy."

Smoking a possible risk factor

The genetic data also makes it easier to differentiate between different forms of the disease. Because there is more than one kind of bipolar disorder: The symptoms and courses of the disease can differ greatly. "We expect there to be different subtypes of the disease, each of which may also require slightly different treatment," Forstner says. "We were for instance able to show that a form of bipolar disorder that is often very severe, called type I, is more strongly related to schizophrenia at the genetic level. In contrast, a somewhat "milder" variant - type II - appears to be more related to depression."

The researchers also compared their findings with the results of studies that search for the genetic basis of certain behaviors. In the process, they came across interesting links: For example, smoking appears to significantly increase the risk of bipolar disorder. In the case of problematic alcohol consumption, however, the analyses suggest a bidirectional relationship: People with a predisposition to bipolar disorder drink more often; conversely, this behavior also appears to increase their likelihood of developing the disorder. "However, we advise caution in interpreting these findings," Forstner explains. "The demonstrated associations between certain behaviors and bipolar disorder first need to be examined in further, large studies."

The results were only possible thanks to the collaboration of around 320 researchers in an international consortium (Psychiatric Genomics Consortium). In addition to the researchers from Bonn, participants in the analyses also included a German-Swiss network with the Central Institute of Mental Health in Mannheim (Prof. Dr. Marcella Rietschel), the University Hospital of Munich (LMU, Prof. Dr. Thomas G. Schulze) and the University Hospital Basel (Prof. Dr. Sven Cichon). Prof. Nöthen is a member of the Transdisciplinary Research Area "Life and Health" at the University of Bonn as well as a member of the ImmunoSensation² Cluster of Excellence.


The study was sponsored by the U.S. National Institute of Mental Health and the National Institute of Health, as well as numerous other institutions. In Germany, the project received funding from the DFG, the BMBF and the Dr. Lisa Oehler Foundation, among others.

Publication: Niamh Mullins, Andreas J. Forstner et al.: Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nature Genetics, DOI: 10.1038/s41588-021-00857-4

Jun.-Prof. Dr. Andreas Forstner
University Hospital Bonn
Institut für Humangenetik
Phone: +49-228-6885-412
Email: forstner@uni-bonn.de

Prof. Dr. Markus M. Nöthen
University Hospital Bonn
Direktor des Instituts für Humangenetik
Phone: +49-228-28751100
Email: markus.noethen@uni-bonn.de

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