By Carol Morton
3 June 2021. The largest genome-wide study of bipolar disorder to date has doubled the genetic markers associated with risk of this mental health disorder.
The findings link well-known medications to the biology, identify new therapeutic leads, and point to certain genes and biological pathways for research priority.
Researchers also found genetic distinctions between two types of bipolar disorder (type I and type II) as well as genetic correlations with other psychiatric disorders, particularly schizophrenia and major depression. An analysis of subtypes found that bipolar type I genetics overlapped more with schizophrenia, while bipolar type II had stronger genetic ties to major depression.
The genome-wide association meta-analysis, published 17 May 2021 in Nature Genetics, included nearly 42,000 cases of bipolar disorder, plus more than 370,000 controls of European ancestry. It is the third analysis of bipolar disorder from the Psychiatric Genomics Consortium (PGC), one of the largest international collaborations in psychiatry.
The study size heralds a new era of risk variant discovery as a tool to understand the disorder etiology and form the basis for development of new prevention and therapeutic strategies, the authors say.
“It generates bigger statistical power to find the genetic variants associated with the diagnosis of bipolar disorder,” says senior author Ole Andreassen, professor of psychiatry, Institute of Clinical Medicine and Oslo University Hospital, who chairs the PGC bipolar disorder working group. “At this level, we can find many common genetic variants and start to look at the related biology.”
Nordic Contributions
Nordic cohorts have been instrumental to the success of the PGC, since the earliest PCG bipolar disorder genetic studies, Andreassen says. Follow-up studies in the Nordic countries may be able to illuminate the longitudinal development of bipolar disorder and outcomes over lifespans. He and his colleagues have European Union grants to provide the infrastructure enabling safe and secure analyses of Swedish, Finnish, Icelandic, Norwegian, Danish, and Estonian national registry data and biobanks.
Bipolar disorder runs in families. Previous research suggests more than one-half of the risk comes from genetic factors, but it has been difficult to identify the genetic variants that confer susceptibility. Environmental factors likely also play a role, according to the PGS website. Most people with close relatives with bipolar disorder won’t develop the condition.
“Genetics is not the whole answer,” Andreassen says. “But genetics can help us figure out more about the environmental stressors. There is a big opportunity in the Nordic region for that.”
In the new paper, one set of calculations supports a role of sleep habits, and alcohol and substance usage in the development of bipolar disorder, although further research is needed to confirm these findings.
"Our study found DNA variations involved in brain cell communication and calcium signaling that increase risk of bipolar disorder,” said first author Niamh Mullins, in a news release from Icahn School of Medicine at Mount Sinai, where she is assistant professor of psychiatric genomics. Mullins is also the data access representative for the PGC bipolar workgroup.
“The findings suggest that drugs, such as calcium channel blockers that are already used for the treatment of high blood pressure and other conditions of the circulatory system, could be investigated as potential treatments for bipolar disorder,” she continued. “Yet it's important to note that future research to directly assess whether these medications are effective is essential."
Also called “manic-depressive illness,” bipolar disorder involves periods of clear changes in mood, energy, and activity levels that can range from energized, irritable, or delusional manic highs to sad, indifferent, or hopeless depressive lows. Symptoms can last for several weeks, causing significant distress and interfering with daily life. Bipolar disorder type 1 is defined by periods of severe mania as well as depressive episodes, and sometimes both. Bipolar type II features depression with less severe manic episodes.
“This GWAS marks an inflection point in risk variant discovery, and we expect that, from this point forward, the addition of more samples will lead to a dramatic increase in genetic findings,” the authors write in the paper. “Nevertheless, fewer genome-wide significant loci have been identified in bipolar disorder than in a schizophrenia GWAS of comparable sample size. This may be due to the clinical and genetic heterogeneity that exists in bipolar disorder.”
The previous PGC bipolar study in 2019 combined 32 cohorts from Europe, North America, and Australia, totaling more than 20,000 cases and more than 31,000 controls of European descent. The new analysis features 57 cohorts totaling twice as many people with bipolar disorder.
Findings from the latest study overlapped with a large East Asian study, the researchers report. And polygenic risk scores overall explained almost 5% across European cohorts, but less than half that in Japanese, Korean, and African American cohorts. The PGC bipolar workgroup plans to include a much bigger non-European sample in the next round of bipolar genetic analysis, including Asian and African cohorts, to capture different genes and to ensure that any clinical applications will benefit all ancestries.
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