Almost 300 genome regions increase risk of bipolar disorder

An international team of psychiatric genetics researchers has identified 298 regions of the genome containing DNA variations that increase risk for bipolar disorder, in the first large multi-ancestry genomic analysis of the disorder to include data from people of European, East Asian, African American and Latino ancestries. Their work has been published in the journal Nature.

Bipolar disorder is an often lifelong mood disorder that impairs quality of life and functional ability, and is associated with suicidality. Bipolar disorder type 1 is characterised by episodes of both mania and depression, while bipolar disorder type 2 includes episodes of hypomania (a less severe form of mania) and depression.

To help elucidate bipolar disorder’s underlying biology, scientists from the international Psychiatric Genomics Consortium conducted a genome-wide association study, scanning the DNA of 2.9 million study participants from cohorts worldwide to identify genetic markers that were more common in those with the condition. This involved scanning more than 6.7 million common variations in the DNA sequences among the study participants, more than 158,000 of whom experience bipolar disorder.

As well as identifying the 298 genome regions that increase risk — a more than fourfold increase over the number previously identified — the researchers also found a new region associated with an increased risk within the East Asian samples. Cross-referencing a range of methods, including fine-mapping and other variant-to-gene-mapping approaches, the team identified 36 genes suspected to be relevant to bipolar disorder.

“It is well established that bipolar disorder has a substantial genetic basis, so identifying DNA variations that increase risk is of paramount importance to understanding the condition’s genetic architecture,” said Assistant Professor Niamh Mullins from the Icahn School of Medicine at Mount Sinai, a senior author on the paper.

“In addition to identifying 298 regions of the genome that contain variations that increase risk for bipolar disorder, the 36 key genes we identified as being linked to the condition can now be followed up in a range of experiments to uncover the biological mechanisms through which each relates to the disorder.

“The newly identified genes may also be used in experiments to explore new drug targets and drug development for bipolar disorder.”

The study team also found differences in the genetic characteristics of bipolar disorder between clinical (patients recruited from hospital inpatient or outpatient units), community-based (participants in general population biobanks) and self-reporting (participants in online personal health surveys) participants. These genetic differences are likely to be driven by a higher prevalence of bipolar subtype 1 in the clinical samples versus a higher prevalence of bipolar subtype 2 in the self-reporting samples, which highlights the need for researchers to be mindful of the data-gathering strategies used within their studies of the condition.

According to the research team, the genetic signal of bipolar disorder is related to specific brain cell types, including GABAergic interneurons and medium spiny neurons, in the prefrontal cortex and hippocampus. They also found that cells in the intestine and pancreas are involved, although more research is necessary to further understand this biology.

Senior author Professor Ole Andreassen, from Oslo’s Institute of Clinical Medicine, concluded, “Our research paves the way for the development of improved treatments, earlier interventions and precision medicine approaches that will support clinicians in their decision-making to enable them to manage the condition in the most effective way for each patient.”

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