01/31/2025

Understanding Bipolar Disorder Through The Genome

12:00 minutes

Two faces facing away from each other, each with a graphic of DNA overlaid over their heads.
Image made with elements from Canva.

Bipolar disorder is one of the most common mental illnesses—it affects an estimated 40 million people worldwide, about 2.8% of the population. Bipolar disorder can cause extreme mood swings, and be debilitating without treatment.

In an effort to untangle the mysteries of where bipolar disorder originates, researchers studied the genomes of more than 158,000 people with the condition. When comparing these genomes to those of people without bipolar disorder, the researchers were able to pinpoint 298 different parts of the genome associated with the mental illness. With this better understanding of the genome, better, more targeted treatments for bipolar disorder may be possible.

Joining Flora to talk about this research is Dr. Niamh Mullins, assistant professor of psychiatric genomics at the Icahn School of Medicine at Mount Sinai in New York.


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Segment Guests

Niamh Mullins

Dr. Niamh Mullins is an assistant professor of Psychiatric Genomics in the Icahn School of Medicine at Mount Sinai in New York, New York.

Segment Transcript

FLORA LICHTMAN: This is Science Friday. I’m Flora Lichtman. Later in the hour, we’ll check in on some quantum computing advances, plus a new technology that blends bioluminescence with cellular machines to shine some light on how our bodies work. But first, a new study on bipolar disorder, a condition that’s characterized by extreme mood swings, including sometimes manic episodes, followed by bouts of depression.

Despite the fact that bipolar disorder affects 40 million people worldwide, it’s often misdiagnosed. And its underlying biology isn’t fully understood. A new study is filling in some gaps. Researchers looked at the DNA of almost 3 million people and found new regions of the genome associated with the condition.

Here to tell us more about what these findings might mean for treatment and our understanding of bipolar disorder is my guest, Dr. Niamh Mullins, assistant professor of psychiatric genomics at the Icahn School of Medicine at Mount Sinai in New York. Welcome to Science Friday, Niamh.

NIAMH MULLINS: Thank you. Glad to be here.

FLORA LICHTMAN: So tell me a little bit about what you found in this study.

NIAMH MULLINS: In this study, we found 298 genomic regions linked to bipolar disorder. So each of these regions is a window into the biology of the disorder. Each one can include many genes. And we did a variety of analyses to map the genetic variants in these regions to particular genes. And this allowed us to identify 36 genes that had robust evidence for their involvement in the disorder.

FLORA LICHTMAN: 36 genes– so is that a lot? Was that what you were expecting?

NIAMH MULLINS: We know that bipolar disorder is very polygenic. So there’s no one risk gene. But there’s many risk variants throughout the genome that each increase risk by a tiny amount. So we expect that there are many genes involved in risk for the disorder.

FLORA LICHTMAN: So you found 298 regions associated with 36 genes. Were many of these new? Had we known about them before?

NIAMH MULLINS: Of these 298 regions, 267 of them have been linked to bipolar disorder for the first time in this study. So it’s a four-fold increase in the number of regions that were known previously. And that’s thanks to being able to conduct this larger study, including many more participants.

FLORA LICHTMAN: A four-fold increase? I want to understand this. Is that because we’ve never sampled this many people before or the sampling methods have gotten better? How do you explain that jump?

NIAMH MULLINS: It’s really driven by the number of participants in the study. So every genetic study is a mixture of signal and noise. And we need enough participants in the study so that signal outweighs the noise and we’re able to detect the regions of the genome involved. And since each of these genetic variants confers a very small effect on risk, we needed hundreds of thousands of samples to be able to detect these regions.

FLORA LICHTMAN: Were any of the regions surprising, or were they associated with other things that add up for what we know about bipolar disorder?

NIAMH MULLINS: Many of the genes that we identified have roles in synaptic signaling– so communication between different cells in the brain. And we did also see in this study some evidence of the involvement of certain cell types outside of the brain. So we saw two cell types highlighted from the intestine and the pancreas. And so this was a novel finding for the first time, pointing us towards some cell types outside of the brain. And we do know some of these cell types are capable of producing serotonin, which affects circulating serotonin and brain serotonin levels. So it’s pointing us towards an involvement of the gut-brain axis. But we do need further research to better understand the potential mechanism underlying this.

FLORA LICHTMAN: Wow. So the pancreas and the intestines might be involved in bipolar disorder?

NIAMH MULLINS: Yes. This is what the current data suggests, a link there between the gut-brain axis, which was a surprising finding from this study. It’s not something that had come up previously in our previous genetic studies of the disorder. So there’s definitely something novel there to explore in future studies.

FLORA LICHTMAN: Are all these genetic regions equally predictive for the illness?

NIAMH MULLINS: Some of them increase risk for the disorder more than others. So one of the ways these genetic studies could have an impact is in building genetic risk predictors for bipolar disorder, or polygenic risk scores. So these are scores that summarize an individual’s genetic risk for bipolar disorder based on the results of this study.

And so the genetic regions can increase risk by different amounts. But really, we want to look at the risk across the entire genome. And we sum that together to create a polygenic risk score, which is a single number which summarizes a person’s genetic risk for the disorder.

FLORA LICHTMAN: And are there multiple presentations of bipolar disorder? And do they correlate, somehow, with these different regions? If you have changes in different regions, do you have a different presentation of the condition?

NIAMH MULLINS: We know that bipolar disorder is heterogeneous clinically. So there are different presentations. For example, there are subtypes. And type I bipolar disorder is characterized by manic episodes and depressive episodes, whereas type II bipolar disorder is characterized by hypomanic episodes and depressive episodes.

So we also see some differences on the genetic level. We’ve been able to study type I and type II bipolar disorder separately. And what we see is that they’re highly genetically similar. But they’re not genetically identical. So some differences on the genetic level could partially explain the differences in clinical presentations for people who experience bipolar disorder.

FLORA LICHTMAN: So let’s talk about the applications for this research. And you touched on them a little bit. But do you see this research underpinning a new genetic test for diagnosing bipolar disorder?

NIAMH MULLINS: We won’t be able to use a genetic test to diagnose bipolar disorder because it’s not completely genetic. So when we think about genetic tests, we need to think about them as tests for a genetic risk or a genetic susceptibility.

Currently, the genetic risk predictors that we’re able to construct based on genetic studies– they’re not yet powerful enough to be used in clinical practice. But we do know that the performance of these genetic risk predictors will continue to improve as we conduct larger and more powerful genetic studies.

And so there are a number of possibilities in the long term for being able to use tests for genetic risk in clinical practice. And there are some studies ongoing incorporating genetic risk predictors into clinical care, and particularly for physical disorders, such as breast cancer or heart disease, to investigate how useful these genetic risk predictors could be in terms of stratifying patients who would benefit from earlier screening or earlier intervention to reduce their risk. So I expect that we’ll see more studies in psychiatry in the next few years to investigate how useful polygenic risk scores could be in informing clinical care in terms of assisting with the diagnosis, early intervention, perhaps even treatment selection, alongside the current clinical tools.

FLORA LICHTMAN: Do these findings point to new treatments?

NIAMH MULLINS: Yes. We’ve seen, based on the 36 genes that we identified in this study, that many of the proteins encoded by these genes can be targeted by drugs. Some are actually the targets of existing medications that are currently in use for treating other disorders. So there could be opportunities for repurposing some medications for treating bipolar disorder. And there could be some novel drug targets amongst these genes.

Of course, we need further research into each of these drug targets– of course, clinical trials before any new medications could be used in patient care. But the results so far are promising. And we know that drugs that have genetic support for their target or their mechanism of action have a higher chance of success in the drug development pipeline. So that’s encouraging.

FLORA LICHTMAN: If we zoom out for a minute, how well-understood is bipolar disorder?

NIAMH MULLINS: Until recent years, our knowledge about the genetics of bipolar disorder has lagged behind other psychiatric disorders, like schizophrenia or autism, which receive more attention and more research funding. But in the last few years, that’s really started to change. Our studies on bipolar disorder have rapidly grown to now including hundreds of thousands of participants, which has enabled us to identify these 298 genomic regions involved. So it’s slightly surpassed similar genetic studies on schizophrenia. And our knowledge base on the genetics and biology has really started to improve in the last couple of years.

FLORA LICHTMAN: Why has it lagged behind?

NIAMH MULLINS: It’s received less attention, less research funding than some other psychiatric disorders. The studies on bipolar disorder were smaller than those of other psychiatric disorders. And coming back to that heterogeneity that you mentioned in clinical presentation, again, we need really large sample sizes in order for the signal to outweigh the noise in the genetic studies and be able to detect these regions that are involved in the disorder.

So it’s really a combination of increasing sample size through international collaboration. In this study, we meta-analyzed the results from 79 different studies from all around the world. So it’s bringing together all of that data through international collaboration. Having more funding to be able to do this work has really driven the knowledge forward.

FLORA LICHTMAN: Does stigma around mental illness and around this disorder prevent us from doing these studies, or has it contributed to the lag in our understanding of them?

NIAMH MULLINS: Yes, there’s certainly stigma still surrounding psychiatric disorders. But I think that understanding the genetics and biology of these disorders could actually contribute to reducing the stigma surrounding them– so having a better understanding of how these conditions arise. And participants in these studies often find it very meaningful to be involved in the research. Even if it doesn’t impact them directly right now, it may have impact in the future for other patients. And so contributing to these genetic studies is a way that I think we can reduce the stigma surrounding bipolar disorder and other psychiatric disorders.

FLORA LICHTMAN: That’s about all the time we have for today. Thank you so much for joining us.

NIAMH MULLINS: Thank you for having me.

FLORA LICHTMAN: Dr. Niamh Mullins, assistant professor of psychiatric genomics at the Icahn School of Medicine at Mount Sinai in New York.

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