Researchers at King’s College London and the University of Florence have identified, for the first time, the specific genetic blueprint for mania, the defining characteristic of bipolar disorder.
Bipolar disorder is one of the most serious and complex psychiatric conditions, affecting approximately 2% of people worldwide. While episodes of depression, psychosis, and other symptoms are common, mania is what distinguishes bipolar disorder from other mental illnesses. Mania is a state of persistently elevated or irritable mood characterized by increased energy, decreased need for sleep, rapid thoughts and speech, and, in some cases, decreased judgment, impulsive behavior, or psychotic symptoms. Until now, however, the biology of mania has been difficult to study because many people diagnosed with bipolar disorder also have episodes of depression and psychosis, making it difficult to determine what is specific to bipolar disorder itself.
To uncover the genetic basis of mania, the researchers used data from very large international genetic studies, including more than 27,000 people with severe bipolar disorder and more than 576,000 people studied for depression. They applied an advanced statistical approach that allowed them to separate the genetic signals for mania from those for depression. Simply put, this method works by subtracting the genetic effects associated with depression from those seen in bipolar disorder, leaving behind the genetic component specific to mania. This made it possible to study mania as its own biological process for the first time.
The study found that mania accounted for more than 80% of the genetic variation in bipolar disorder, highlighting its central role in the condition. The researchers identified 71 genetic variants specifically linked to mania, including 18 gene regions that had never previously been associated with bipolar disorder. Many of these genes are involved in voltage-gated calcium channels, which are essential for communication between brain cells and for mood regulation. When compared genetically with other traits, mania showed a distinct profile, sharing less genetic overlap with substance use and more with measures related to well-being and educational attainment than bipolar disorder as a whole.
Understanding the genetics of mania is extremely important because it offers a direct window into the basic biology of bipolar disorder. Many people with bipolar disorder first seek help during depressive or other types of episodes, when the condition may closely resemble severe depression or schizophrenia. As a result, individuals can spend up to a decade moving between different diagnoses before bipolar disorder is properly diagnosed. By defining the genetic characteristics unique to mania, this research brings the field closer to identifying early biological markers of bipolar disorder, with the potential to shorten that diagnostic journey and ensure people receive the right treatment sooner.
Important implications for diagnosis and treatment
These findings have important implications for diagnosis and treatment. Psychiatrists currently distinguish between different forms of bipolar disorder, such as Bipolar I, Bipolar II, and cyclothymia, based largely on patterns of mood episodes over time. A clearer understanding of the biology of mania may help refine these distinctions, identify additional subtypes, and support more personalized approaches to care. The results also highlight potential treatment pathways, including calcium channel mechanisms, and suggest that established drugs such as lithium may exert their effects through these biological systems.
Dr Giuseppe Pierpaolo Merola, MRC Clinical Research Training Fellow, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, lead author of the study, said: “By isolating the genetic architecture of mania, we have taken a critical step towards understanding the basic biology of bipolar disorder. mixture of mania, depression and psychosis and opens up new possibilities for more precise and personalized treatments.”
Professor Gerome Breen, Professor of Psychiatric Genetics at King’s College London and Mental Health BioResource Lead at the NIHR Maudsley Biomedical Research Centre, said: “Mania is what defines bipolar disorder, yet it remains surprisingly difficult to study on its own. Our research into the genetics of rage gives us a clear picture of the genetics of rage. In the long term, this could help clinicians recognize bipolar disorder earlier, reduce the long delays many patients experience before receiving a diagnosis, and improve outcomes through more targeted treatment.
The research was conducted at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London in collaboration with the University of Florence. Funded by the National Institute for Health and Care Research Maudsley Biomedical Research Centre. The study was published on January 28, 2026 in Biological Psychiatry.
