REYKJAVIK, Iceland, March 25, 2025 /PRNewswire/ -- Bipolar disorder, a condition marked by extreme mood swings—including manic or hypomanic episodes and bouts of depression—has been a focus of extensive research due to its high heritability and significant impact on individuals and society. Today, scientists at deCODE genetics, a subsidiary of Amgen, announced in Nature Genetics their discovery of associations between rare loss-of-function (LOF) variants in two specific genes, HECTD2 and AKAP11, and bipolar disorder.
This study involved an ambitious variant burden analysis utilizing whole genome sequencing data from Iceland, which included 4,197 cases compared to over 200,000 controls, and the UK Biobank, with 1,881 cases and 426,622 controls. The findings revealed compelling evidence supporting the hypothesis that these rare genetic variants contribute significantly to the risk of developing bipolar disorder.
Bipolar disorder carries a global prevalence rate of approximately 2%, and its heritability is estimated to be between 60% and 85%, according to twin and family studies. Over the past 15 years, genome-wide association studies (GWAS) have identified numerous common genetic variants associated with psychiatric disorders. However, the current study focused on rare LOF variants that offer deeper insights into the underlying biology of bipolar disorder.
Dr. Thorgeir Thorgeirsson, a lead investigator at deCODE genetics, explained, "Our research highlights the medical significance of rare genetic variants. While they are often overlooked due to their infrequency, they can provide critical insights into the biology of conditions like bipolar disorder." He further noted that both HECTD2 and AKAP11 are novel associations with bipolar disorder, although AKAP11 has previously been implicated in studies of psychosis and schizophrenia.
In further detail, the study employed gene-based aggregation methods to analyze the burden of LOF variants in 13,786 different genes. The researchers found that combined rare LOF variants in HECTD2 exhibited a significant association with bipolar disorder, showing a frequency of 0.011%, with an odds ratio of 9.1 and a p-value of 4.7 × 10−7. This robust effect was confirmed through a meta-analysis with additional data from the Bipolar Exome dataset (BipEx), which further demonstrated that LOF variants in AKAP11 were also associated with bipolar disorder, presenting an odds ratio of 11.8 and a p-value of 7.4 × 10−9.
AKAP11 is known to play a critical role in sectioning protein kinase A (PKA) within cells, facilitating the regulation of various signaling pathways, while HECTD2 functions as an E3 ubiquitin ligase. Both gene products are involved in the modulation of GSK3β, a protein previously identified as a key target of lithium, the most effective treatment currently available for bipolar disorder.
The implications of these findings extend beyond just identifying genetic risk factors. The research suggests a potential therapeutic direction, as Dr. Thorgeirsson pointed out: "Understanding how specific rare variants like those in HECTD2 and AKAP11 interact with GSK3β opens up pathways for developing new treatments that could be more effective and have fewer side effects than existing medications."
Bipolar disorder, if left untreated, can lead to severe outcomes, including suicide, making the urgency for improved, tailored treatments even more pronounced. Currently available mood stabilizers carry various side effects, highlighting the need for more effective options.
The study not only confirms the role of rare LOF variants in bipolar disorder but also suggests that they may be responsible for a significant part of the genetic variance observed. With prospective estimates indicating that 64 genomic loci are associated with the disorder, further studies could uncover even more insights about the biological mechanisms at play.
Moreover, individuals diagnosed with bipolar disorder exhibited a notably lower general cognitive performance when compared to control groups, with statistical analyses revealing an effect size of -0.40 (p = 1.0 × 10−18). Among carriers of HECTD2 LOF variants, there was also evidence suggesting a lower cognitive function, indicated by an effect size of -0.38 (p = 0.030) in those not diagnosed with the disorder.
The methodology behind these findings is solidified by the integration of large-scale genetic datasets that allow for robust analyses. With a combination of genome-wide sequencing techniques and comprehensive phenotypic data collection, the collaboration of deCODE genetics with international databases empowers researchers to draw credible conclusions about genetic associations.
In conclusion, the discovery of associations between rare LOF variants in HECTD2 and AKAP11 with bipolar disorder marks a significant advance in psychiatric genetics. As research evolves, these findings could reshape approaches to treating bipolar disorder, offering hope not just for patients, but for families grappling with the challenges this disorder presents. The path ahead appears promising, grounded in genetic insights that may one day lead to tailored treatments, ultimately transforming the landscape of bipolar disorder management.
