Rare loss-of-function variants in HECTD2 and AKAP11 confer a risk of bipolar disorder

Scientists at deCODE genetics, a subsidiary of Amgen, reveal today in Nature Genetics associations between rare loss-of-function variants in two genes and bipolar disorder.

REYKJAVIK, Iceland, March 25, 2025 /PRNewswire/ -- Bipolar disorder is characterized by extreme mood swings, bouts of mania or hypomania, and episodes of depression.  It is a highly heritable and serious condition, that when untreated comes with a high suicide rate.  While there are several mood-stabilizing drugs available to treat the disorder, pharmaceutical treatment of bipolar disorder can have difficult side-effects and better treatments are urgently needed.

Significant progress has occurred over the last 15 years through genome-wide association studies leading to the identification of hundreds of biomarkers, i.e. DNA sequence variants, associated with the risk of psychiatric disease, including bipolar disorder.  These biomarkers represent common variations each carrying a small risk, but in confluence, they are beginning to account for a considerable part of the variance in psychiatric traits and disorders. Variants predicted to cause loss of function of genes tend to be rare but hold great promise for informing on the underlying biology.   

To harness the information contained in rare loss-of-function (LOF) variants, the scientists performed a variant burden analysis for bipolar disorder using gene-based aggregation of LOF variants in whole genome sequencing data from Iceland and the UK Biobank and using data from the Bipolar Exomes study (BipEx, www.bipex.broadinstitute.org/results) for replication and further meta-analysis efforts. The study revealed the association of LOF variants in two genes (HECTD2 and AKAP11) with bipolar disorder. Both associations with bipolar disorder are novel, but AKAP11 has previously been associated with psychosis and schizophrenia. 

AKAP11 encodes an anchoring protein, that regulatory subunits of protein kinase A (PKA) bind to, leading to confinement of PKA to specific cellular locations.  HECTD2 encodes an E3 ubiquitin ligase, that adds multiple ubiquitin groups to proteins, thereby labeling them for destruction by the proteasome.    The products of both AKAP11 and HECTD2 interact with GSK3β, a protein inhibited by lithium, the most effective mood stabilizer available to treat bipolar disorder.  These findings point to the dysfunction of specific cellular pathways in bipolar disorder and cast the gene products of AKAP11 and HECTD2 along with GSK3β as promising targets in the search for new treatments for bipolar disorder. 

Based in Reykjavik, Iceland, deCODE genetics is a global leader in analyzing and understanding the human genome. Using its unique expertise and population resources, deCODE has discovered genetic risk factors for dozens of common diseases. The purpose of understanding the genetics of disease is to use that information to create new means of diagnosing, treating and preventing disease. deCODE genetics is a wholly-owned subsidiary of Amgen.

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