Study published in Nature identifies nearly 300 genomic regions associated with bipolar disorder, and 36 key genes involved in the disease. The biological insights from this research could pave the way for developing improved treatments, earlier interventions and precision medicine approaches.

Bipolar disorder is a complex psychiatric disorder, characterized by fluctuations between episodes of (hypo)mania and depression. It is estimated to affect around 40 to 50 million people worldwide. The disorder has been linked to a number of negative outcomes, including suicide, and it can take an average of 8 years to get a diagnosis. Yet, little is known about the biology of the condition.

A new study of nearly 2.9 million participants identified 298 genomic regions associated with bipolar disorder, of which 298 regions have not been linked to bipolar disorder before. Cross-referencing a range of methods lead to the identification of 36 genes of relevance to bipolar disorder. The findings are published in the journal Nature.

“This is the first large multi-ancestry genomic analysis of bipolar disorder, including different types of bipolar disorder. Due to the large sample size, the study greatly increased genetic discovery to nearly 300 genetic variants associated with bipolar disorder”, says researcher Kevin O’Connell at the Centre for Precision Psychiatry at the University of Oslo, and first author of the study. “These genetic findings improve our understanding of the underlying biological mechanisms for bipolar disorder”.

Differences in the molecular biology between bipolar subtypes
The researchers further identified differences in the genetic signal of bipolar disorder based on if they were recruited from clinical, community-based and self-report samples. They also found different genetic signals between subtypes I and II. Self-reported samples showed more genetic overlap with bipolar disorder type II as well as other psychiatric disorders such as major depressive disorder, post-traumatic stress disorder and autism spectrum disorder. In contrast, clinical samples showed a stronger genetic overlap with bipolar disorder type I and schizophrenia.

“These results suggest that there are differences in the molecular biology between bipolar subtypes, which is important for future research, as well as clinical implications”, says Professor Ole Andreassen at the Centre for Precision Psychiatry at the University of Oslo, and lead investigator of the study.

Further analysis suggested a possible role for neurons in the prefrontal cortex and hippocampus of the brain in bipolar disorder. Interestingly, the study also found that cells in the intestine and pancreas are involved. This further contributes to our understanding of the biological etiology of bipolar disorder.

Future patient care
Although this work does not immediately impact patient care, there are a number of possibilities in the long term. “The biological insights from this research could pave the way for developing improved treatments, earlier interventions and precision medicine approaches. Gaining insight into the biological risk factors for bipolar disorder could also support clinicians in their decision making around managing the condition more effectively”, Andreassen states.

The study linked 36 key genes to bipolar disorder which can now be prioritized in a range of experiments to uncover the biological mechanisms through which these genes relate to bipolar disorder. These genes may also be used in experiments exploring new drug targets and drug development for bipolar disorder.

Largest study on the genetics of bipolar disorder to date
This study is the largest genome-wide study of bipolar disorder to date, analysing data from European, East Asian, African American and Latino ancestries.

It was conducted by the Psychiatric Genomics Consortium (PGC), an international consortium of scientists dedicated to studying the genetic basis of psychiatric disorders. The PGC includes more than 800 researchers from over 150 institutions in more than 40 countries (https://www.med.unc.edu/pgc/).

“This research would not be possible without the collaborative efforts of scientists worldwide, enabling the study of hundreds of thousands of DNA sequences. A strong team of young researchers was responsible for the analyses and thus was essential for the success of the project”, O’Connell says.