Summary: Researchers have pinpointed 64 genomic regions that contain DNA variations linked to increased risk for bipolar disorder and have shown genetic overlap with other psychiatric conditions.
Source: Mount Sinai Hospital
In the largest genetic study of bipolar disorder to date, an international team of researchers has identified 64 genomic regions where DNA variations are associated with higher risk for bipolar disorder—more than doubling the number of loci reported previously.
The study also reveals a shared genetic architecture between bipolar disorder and other psychiatric illnesses. In addition, the results point to potential links between bipolar disorder risk and behaviors such as sleep patterns, alcohol use, and substance use, although further work is needed to confirm and clarify these relationships.
These findings were published May 17 in Nature Genetics.
Bipolar disorder is a complex psychiatric condition marked by recurrent episodes of elevated and depressed mood. It affects an estimated 40 to 50 million people worldwide, typically begins in young adulthood, often follows a chronic course, and carries an elevated risk of suicide—making it a significant global public health concern and contributor to disability.
To uncover biological contributors to bipolar disorder, scientists from the Psychiatric Genomics Consortium conducted a genome-wide association study (GWAS). This approach scans large numbers of genetic markers across many individuals to identify variants that occur more frequently in people with the disorder.
The analysis examined more than 7.5 million common genetic variants in nearly 415,000 people, including over 40,000 individuals diagnosed with bipolar disorder. From this dataset, the researchers identified 64 genomic loci that contain DNA variations linked to increased risk of bipolar disorder.
“It is well established that bipolar disorder has a substantial genetic component, and locating the specific DNA variations that increase risk gives us crucial clues about the biology behind the illness,” said Niamh Mullins, PhD, Assistant Professor of Psychiatric Genomics at the Icahn School of Medicine at Mount Sinai and lead author of the study. The team highlighted variants that affect neuronal communication and calcium signaling pathways as contributors to bipolar disorder risk.
Those biological signals raise the possibility that medications affecting calcium channels—such as calcium channel blockers currently used for cardiovascular conditions—warrant further investigation as potential treatments for bipolar disorder. The researchers emphasize that rigorous clinical studies are required to test whether such drugs are safe and effective for this purpose.
The analysis also clarifies genetic relationships among bipolar disorder subtypes and other psychiatric diagnoses. The investigators report a strong genetic similarity between bipolar I disorder and schizophrenia, while bipolar II disorder shows a closer genetic relationship to major depressive disorder. These findings support the idea of both shared and distinct genetic influences across psychiatric conditions and subtypes.
“This research was only possible because of the global collaboration that allowed us to analyze hundreds of thousands of DNA samples,” said Ole Andreassen, MD, PhD, Professor of Psychiatry at the Institute of Clinical Medicine and Oslo University Hospital, and a senior author on the paper. “We have now prioritized specific genes and variants that can be examined in laboratory studies to understand how they increase risk for bipolar disorder.”
Integrating genetic association results with gene expression data, the study implicates genes expressed in neurons—particularly in the prefrontal cortex and hippocampus—and identifies enrichment in synaptic signaling pathways. The researchers also report signal enrichment among genes that are targets of existing drug classes, including antipsychotics, calcium channel blockers, antiepileptics, and anesthetics, pointing to potential therapeutic leads.
These biological insights could support the development of new treatments or precision medicine approaches that identify individuals at elevated genetic risk and tailor interventions accordingly. However, translating genetic discoveries into clinical care will require additional functional studies and well-designed clinical trials.
The authors note that future genetic studies need to include larger and more diverse populations to capture the full range of risk variants across different ancestries and to refine the list of genes that contribute to bipolar disorder.
The Psychiatric Genomics Consortium (PGC) is an international collaboration of researchers focused on the genetics of psychiatric disorders. The consortium includes more than 800 investigators from over 150 institutions in more than 40 countries.
About this genetics and bipolar disorder research news
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
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Original Research: Closed access.
“Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology” by Niamh Mullins et al. Nature Genetics
Abstract
Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
Bipolar disorder is a heritable psychiatric illness with a complex etiology. The investigators performed a genome-wide association study including 41,917 bipolar disorder cases and 371,549 controls of European ancestry, identifying 64 associated genomic loci.
Risk alleles for bipolar disorder were enriched in genes involved in synaptic signaling and in genes highly expressed in neurons—especially neurons of the prefrontal cortex and hippocampus. Significant enrichment also appeared among genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics, and anesthetics.
Integration with expression quantitative trait locus (eQTL) data implicated 15 genes whose expression changes are robustly linked to bipolar disorder, including druggable targets such as HTR6, MCHR1, DCLK3, and FURIN. Analyses of bipolar disorder subtypes revealed a high but imperfect genetic correlation between type I and type II and identified additional associated loci.
Overall, these results advance understanding of the biological basis of bipolar disorder, highlight potential therapeutic leads, and prioritize genes for further functional study.