Study isolates mania-specific genetic architecture in bipolar disorder

Researchers at King's College London and the University of Florence have, for the first time, identified the specific genetic blueprint of mania, the defining feature of bipolar disorder.

Bipolar disorder is one of the most severe and complex psychiatric conditions, affecting around 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 marked by increased energy, reduced need for sleep, rapid thoughts and speech, and, in some cases, impaired judgement, impulsive behaviour or psychotic symptoms. Until now, however, the biology of mania has been difficult to study because many people with a diagnosis of bipolar disorder also have episodes of depression and psychosis, making it hard 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 over 576,000 individuals studied for depression. They applied an advanced statistical approach that allowed them to separate the genetic signals for mania from those for depression. In simple terms, this method works by subtracting the genetic effects associated with depression from those seen in bipolar disorder, leaving behind the genetic component that is specific to mania. This made it possible to study mania as its own biological process for the first time.

The study found that mania accounts for more than 80% of the genetic variation in bipolar disorder, underlining its central role in the condition. The researchers identified 71 genetic variants linked specifically to mania, including 18 regions of genes 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 regulating mood. When compared genetically with other traits, mania showed a distinct profile, sharing less genetic overlap with substance use and more with measures related to wellbeing and educational attainment than bipolar disorder as a whole.

Understanding the genetics of mania is critically important because it offers a direct window into the core biology of bipolar disorder. Many people with bipolar disorder first seek help during depressive or other types of episodes, when the condition can look very similar to severe depression or schizophrenia. As a result, individuals can spend up to a decade moving between different diagnoses before bipolar disorder is correctly identified. By defining the genetic features that are unique to mania, this research moves the field closer to identifying early biological indicators of bipolar disorder, with the potential to shorten this 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 several forms of bipolar disorder, such as Bipolar type I, Bipolar type II and cyclothymia, largely based 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 personalised approaches to care. The results also highlight potential treatment pathways, including calcium-channel mechanisms, and suggest that established medications such as lithium may exert their effects through these biological systems.

By isolating the genetic architecture of mania, we have taken a crucial step towards understanding the core biology of bipolar disorder. This allows us to see what makes mania distinct, rather than viewing bipolar disorder simply as a mixture of mania, depression and psychosis, and opens new possibilities for more precise and personalised treatments."

Dr. Giuseppe Pierpaolo Merola, MRC Clinical Research Training Fellow, Institute of Psychiatry, Psychology & Neuroscience, King's College London, lead author of the study

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 has remained surprisingly difficult to study in its own right. Our research on the genetics of mania gives us a clearer picture of its biology and how it differs from other psychiatric conditions. In the longer term, this could help clinicians recognise bipolar disorder earlier, reduce the long delays many patients face 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. It was funded by the National Institute for Health and Care Research Maudsley Biomedical Research Centre. The study was published on 28 January 2026 in Biological Psychiatry.