Unlocking the Secrets of Bipolar Disorder Through Science

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In one of the most extensive genetic studies to date on Bipolar Disorder, a team of international scientists and researchers at Mount Sinai Icahn School of Medicine identified 36 genes that are linked to the disease. The group was studying the biologic mechanisms that cause Bipolar Disorder. The findings pinpointed 298 specific locations in our DNA sequence, called genomic regions, associated with the disease; 267 are new discoveries (learn more about genes here and DNA here). Characterized by intense mood swings, the disease has long been known to have a genetic predisposition, with an inheritance rate of around 80%. Have scientists been able to unlock the secret to understanding and treating this disease, thereby offering hope to millions?

Clinical presentation of bipolar disease:

Bipolar disorder affects approximately 40 to 50 million people worldwide and can have devastating personal and societal consequences. It is a lifelong, chronic mental health condition characterized by manic (emotional high) and depressive (emotional low) episodes. There is a spectrum of disease intensity, with the most damaging cases resulting in profound effects that can significantly impact both the patient’s life and that of their family. While the severity of the disorder varies, extreme cases can have far-reaching consequences.

A manic episode is characterized by feelings of extreme euphoria, hypersexual behavior, hyperactivity or irritability, and an inability to remain focused or still. When lost in a manic episode, people are prone to extreme insomnia, substance abuse, and hyperspending; they may experience memory loss, potentially losing days from their recollection. During a major depressive episode, individuals can become so depressed that they struggle to leave their beds or engage with society. This period is linked to alarmingly high rates of suicide. In extreme cases of the disorder, homelessness can arise from a person’s inability to function in society.

To be diagnosed with bipolar, one must exhibit signs of mania or hypomania for at least one week. The person must display at least 3–4 characteristics: rapid or pressured speech, marked distractibility, racing thoughts, increased goal-directed activity or agitation, and increased impulsive or high-risk behaviors. Additionally, for the diagnosis to be made, the manic episode must include a marked impairment of social or occupational functioning, psychosis, or hospitalization.

In psychiatric nomenclature, bipolar is broken into two subtypes. Of note, the depression that most people with bipolar disorder experience is not required for a diagnosis of type I. Bipolar I refers to people who suffer from full-fledged manic episodes lasting at least 7 days. They may or may not experience depressive episodes. Bipolar II is characterized by hypomania and recurrent episodes of depression. Hypomania, a less severe form of mania, requires at least four days of symptoms, as well as an apparent change in mood and function, but not necessarily a complete societal breakdown of the patient, as in Bipolar I (Barnett & Smoller, 2009)

How was the study accomplished?

At Icahn Mount Sinai School of Medicine, an international team of genetic psychiatrists carried out a study to pinpoint the biologic pathways and genomic relationships that lead to bipolar disorder. It is the first extensive multi-ancestry genomic analysis of the disease, including people from multiple different nationalities. The scientists from within The Psychiatric Genomics Consortium scanned the DNA of 2.9 million study participants and 6.7 million variants to find biogenetic markers of the condition. The experimental group included tens of thousands of people suffering from bipolar, which were compared to a comparable-sized group of people used as healthy controls. Then, through a series of complicated technological processes, they discovered how these genomic loci might lead to the illness.

Previously, in an article published in Nature, 64 genomic loci and 15 credible genes were found that are thought to play a role in the pathogenesis of bipolar disorder. Surprisingly, the new study found 298 genomic regions containing DNA variations that increase the risk of the disorder. The research also found a new region that shows increased risk in East Asian genes. After cross-referencing a variety of results, using fine-mapping and other variant-to-gene-mapping techniques, 36 genes were found that were definitively linked to bipolar.

The regions in DNA linked to bipolar disorder include areas that can alter how brain cells communicate and regulate calcium in the brain. A rise in intracellular calcium levels, found during mania and depression, can lead to cell damage. Repeated exposure during recurrent episodes ultimately results in permanent damage and cell death. Changes in neuron function and communication have been associated with disruptions in normal brain activity and an increased risk of developing bipolar disorder.

The genetic signal for bipolar disorder was also found by the research team in specific cells located in the brain, intestine, and pancreas, including GABAergic interneurons and medium spiny neurons in the prefrontal cortex and hippocampus. More research is needed to understand this level of biologic underpinnings further.

Bipolar disorder often leads to loneliness and isolation, resulting in poor prognosis and decreased quality of life.

Societal impact of the study:

Despite the prevalence of bipolar disorder, there is still information missing regarding all of its causal factors. It is important to note that, despite the high heritability of the disease, genetic relatability is still not the full picture. Environmental factors, such as stress and trauma, are also recognized to play a noteworthy role in the onset and progression of bipolar disorder. Multiple factors must be considered when determining the most effective therapeutic regimen for the patient, and personalized plans are necessary to ensure a good prognosis.

Continued discoveries arising from this evidence will help clinical doctors identify and treat the disease early. Additionally, this will aid in bringing science to life by allowing the creation of better, more life-changing drugs and therapies with fewer side effects to increase quality of life. The advent of new genetic advances is an inspiring step forward in achieving a more comprehensive understanding of this disorder. Still, more research will be needed to create a holistic approach to treatment, which is undoubtedly the most helpful approach for many psychiatric illnesses. As the future brightens in genetics and neuroscience, there is much to anticipate for the people suffering from these conditions.

Written by: Rachelle DiMedia

References:

Barnett JH, Smoller JW. The genetics of bipolar disorder. Neuroscience. 2009 Nov 24;164(1):331-43. doi: 10.1016/j.neuroscience.2009.03.080. Epub 2009 Apr 7. PMID: 19358880; PMCID: PMC3637882.

Dowling, E. (2025, February 16). Largest genetic study of bipolar disorder identifies 298 regions of the genome that increase risk for the condition. Psychiatric Times. https://www.psychiatrictimes.com/view/largest-genetic-study-of-bipolar-disorder-identifies-298-regions-of-genome-increase-risk

Mayo Clinic. (2023, February 16). Bipolar disorder. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/bipolar-disorder/symptoms-causes/syc-20355955

Mullins, N., Forstner, A.J., O’Connell, K.S. et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet 53, 817–829 (2021). https://doi.org/10.1038/s41588-021-00857-4.

O’Connell, K. S., Koromina, M., van der Veen, T., Boltz, T., David, F. S., Yang, J. M. K., Lin, K.-H., Wang, X., Coleman, J. R. I., Mitchell, B. L., McGrouther, C. C., Rangan, A. V., Lind, P. A., Koch, E., Harder, A., Parker, N., Bendl, J., Adorjan, K., Agerbo, E. … Bipolar Disorder Working Group of the Psychiatric Genomics Consortium. (2025). Genomics yields biological and phenotypic insights into bipolar disorder. Nature. https://doi.org/10.1038/s41586-024-08468-9 

Psychiatric Genomics Consortium. (n.d.). Home. https://pgc.unc.edu/

Wellcome Genome Campus. (n.d.-b). What is DNA? YourGenome. https://www.yourgenome.org/theme/what-is-dna/

Wellcome Genome Campus. (n.d.-a). What is a gene? YourGenome. https://www.yourgenome.org/theme/what-is-a-gene/

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