deCODE genetics, an Amgen subsidiary, has announced in Nature Genetics the discovery of links between rare loss-of-function variants in two genes and bipolar disorder.

REYKJAVIK, Iceland, March 25, 2025 — Bipolar disorder, a highly heritable and severe condition marked by extreme mood fluctuations including mania or hypomania and depression, carries a high suicide risk if left untreated. Current mood-stabilizing drugs often cause challenging side effects, highlighting the urgent need for improved treatments.

Over the past 15 years, genome-wide association studies have significantly advanced the field, identifying hundreds of DNA sequence variants (biomarkers) linked to the risk of psychiatric disorders, including bipolar disorder. These common variations individually pose a small risk, but collectively, they account for a substantial portion of the variability seen in psychiatric traits and disorders. Loss-of-function (LOF) variants, which are predicted to disrupt gene function, are typically rare but offer valuable insights into the underlying biological mechanisms.

To leverage the information from rare LOF variants, researchers conducted a variant burden analysis for bipolar disorder. They aggregated LOF variants at the gene level using whole-genome sequencing data from Icelandic and UK Biobank populations. Data from the Bipolar Exomes study (BipEx) was used for replication and further meta-analysis. The study identified an association between LOF variants in two genes, HECTD2 and AKAP11, and bipolar disorder. While the association with bipolar disorder is new for both genes, AKAP11 has previously been linked to psychosis and schizophrenia.

AKAP11 codes for an anchoring protein that binds to regulatory subunits of protein kinase A (PKA), confining PKA to specific locations within cells. HECTD2 encodes an E3 ubiquitin ligase, which attaches multiple ubiquitin groups to proteins, marking them for degradation by the proteasome. Both AKAP11 and HECTD2 products interact with GSK3β, a protein inhibited by lithium, the most effective mood stabilizer used in bipolar disorder treatment. These results suggest dysfunction in specific cellular pathways contributes to bipolar disorder and identify AKAP11, HECTD2, and GSK3β as potential targets for developing novel treatments.

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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