Researchers at deCODE genetics, a subsidiary of Amgen, have identified two rare gene variants associated with bipolar disorder. Their findings, published in Nature Genetics, could provide fresh insights into the biological mechanisms underlying the condition and pave the way for improved treatments.
Bipolar disorder is a severe psychiatric condition characterised by extreme mood swings, including episodes of mania and depression. It is highly heritable and, if left untreated, carries a significant risk of suicide. While mood-stabilising drugs such as lithium are available, they often come with challenging side effects, underscoring the need for better treatment options.
A new genetic discovery
Over the past 15 years, genome-wide association studies have identified hundreds of common genetic variations linked to psychiatric conditions, including bipolar disorder. However, these common variations each contribute only a small increase in risk. By contrast, rare genetic variants that disrupt the function of specific genes—known as loss-of-function (LOF) variants—can offer valuable insights into disease biology.
To explore this further, scientists at deCODE performed a variant burden analysis using whole genome sequencing data from Iceland and the UK Biobank. Their findings were then replicated and refined using data from the Bipolar Exomes (BipEx) study.
The study identified rare LOF variants in two genes—HECTD2 and AKAP11—as being associated with bipolar disorder. While this is the first time either gene has been linked to the condition, AKAP11 has previously been implicated in psychosis and schizophrenia.
Potential targets for new treatments
AKAP11 encodes a protein that binds to protein kinase A (PKA), a key regulator of cellular activity. Meanwhile, HECTD2 encodes an enzyme involved in protein degradation. Notably, both proteins interact with GSK3β, an enzyme that is inhibited by lithium, the most effective mood stabiliser used in the treatment of bipolar disorder.
These findings suggest that disruptions in specific cellular pathways involving AKAP11, HECTD2, and GSK3β may contribute to the development of bipolar disorder. Scientists believe this knowledge could help identify new drug targets, potentially leading to alternative treatments for the condition.
A step forward in psychiatric genetics
Based in Reykjavik, Iceland, deCODE genetics is recognised as a global leader in genetic research. The company has previously identified risk factors for numerous common diseases by analysing extensive population datasets.
A spokesperson for deCODE said that understanding the genetic basis of bipolar disorder could improve both diagnosis and treatment options in the future.
“By identifying these rare genetic variants, we are uncovering crucial biological pathways that could be targeted for new therapies,” they said.
While further research is needed to confirm these findings and explore their clinical applications, the study marks an important step in understanding the genetic roots of bipolar disorder. Scientists hope that by shedding light on the molecular mechanisms behind the condition, they can contribute to the development of more effective and personalised treatments.