New Insights into the Biological Basis of Bipolar Disorder

An international team of psychiatric genetics researchers has identified 298 regions of the genome containing DNA variations that increase the risk of bipolar disorder—more than four times the number previously known. Published in Nature, this is the largest genome-wide study of bipolar disorder conducted to date.

The study is notable for being the first large-scale, multi-ancestry genomic investigation of bipolar disorder. It incorporates data from individuals of European, East Asian, African American, and Latino ancestry. Among the findings is a novel genomic region associated with an elevated risk of the disorder in East Asian populations. Using advanced methodologies such as fine mapping and variant-to-gene mapping, the team also identified 36 genes likely linked to bipolar disorder.

Bipolar Disorder: A Global Challenge

Bipolar disorder is a chronic mood disorder that significantly impacts quality of life and functional abilities. Affecting approximately 40–50 million people worldwide, the condition is associated with high rates of suicidality and takes an average of eight years to be accurately diagnosed. Bipolar disorder manifests in two main subtypes:

• Type 1: Characterized by episodes of both mania and depression.
• Type 2: Marked by episodes of hypomania (a less severe form of mania) and depression.

Despite its prevalence, much of the biological underpinnings of bipolar disorder remain poorly understood.

Largest Genome-Wide Study to Date

To uncover the genetic architecture of bipolar disorder, an international team of scientists from the Psychiatric Genomics Consortium analyzed data from 2.9 million participants worldwide. Of these, more than 158,000 had a diagnosis of bipolar disorder. The study examined over 6.7 million common DNA sequence variations to identify genetic markers more frequently found in individuals with the condition.

“Bipolar disorder has a significant genetic basis, so identifying DNA variations that increase risk is essential to understanding the condition’s genetic architecture,” said Niamh Mullins, PhD, senior author and assistant professor at Mount Sinai. “The 36 key genes we identified can now be explored further to uncover the biological mechanisms linking them to the disorder.”

Dr. Mullins also highlighted the potential for these discoveries to inform drug development and identify new therapeutic targets for the condition.

Genetic and Clinical Insights

The study also revealed genetic differences based on how participants were recruited:

• Clinical samples (patients from hospital inpatient or outpatient units) had a higher prevalence of bipolar subtype 1.
• Self-reporting samples (individuals who participated through online surveys) showed a higher prevalence of subtype 2.
  These findings emphasize the importance of considering recruitment and data collection methods in genetic studies of bipolar disorder.

The team identified that certain brain cell types—such as GABAergic interneurons and medium spiny neurons in the prefrontal cortex and hippocampus—are linked to the genetic signals associated with bipolar disorder. Interestingly, they also found connections to intestinal and pancreatic cells, though more research is needed to understand these associations fully.

A Step Toward Better Treatments

While these findings do not yet translate directly to clinical care, they lay the foundation for significant long-term benefits. “Our research opens possibilities for developing improved treatments, earlier interventions, and precision medicine approaches that will help clinicians provide personalized care for each patient,” said Ole Andreassen, MD, PhD, senior author and professor at Oslo University Hospital.

The Psychiatric Genomics Consortium, which includes over 1,700 researchers from more than 65 countries, played a crucial role in this effort. Kevin O’Connell, PhD, first author and researcher at the University of Oslo, emphasized the importance of collaboration: “This research was made possible by the combined efforts of scientists worldwide, enabling us to analyze hundreds of thousands of DNA sequences.”

Looking Ahead

This groundbreaking study represents a major step forward in understanding the genetics of bipolar disorder. As scientists continue to build on these findings, the hope is to develop more effective treatments and support systems for the millions affected by this complex condition.