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Exome sequencing in bipolar disorder identifies new risk gene

A study published in Nature Genetics from a consortium of researchers — the BipEx collaboration — is the largest whole-exome study of bipolar disorder to date. The study of almost 14,000 patients with bipolar disorder and over 14,000 controls uncovered a new risk gene that is shared with schizophrenia.

Bipolar disorder is a heritable neuropsychiatric disorder characterized by episodes of mania and often episodes of depression. Two clinical subtypes of bipolar disorder exist, bipolar I disorder, which has genetic overlap with schizophrenia, and bipolar II disorder, which has genetic overlap with major depressive disorder. Although genetics play a big part in bipolar disorder, a large fraction of genetic risk remains undiscovered.

Ultra-rare protein-truncating variants

The researchers found an enrichment of ultra-rare, protein-truncating variants in evolutionarily constrained genes in patients with either type of bipolar disorder. Indeed, the enrichment in the genes remained even after the top 20 bipolar disorder risk-associated genes were excluded. The authors note that this finding reflects the highly polygenic genetic architecture of bipolar disorder, a property that is shared with schizophrenia.

Shared genetic risk with schizophrenia

The researchers then used their results in concert with findings results from two companion papers that identified genetic risk factors for schizophrenia (see below). This part of the bipolar study found that there was also enrichment of ultra-rare protein-truncating variants within genes implicated in schizophrenia. In other words, there are risk genes that are shared between bipolar disorder and schizophrenia.

One particular gene, AKAP11, stood out as a definitive risk gene in both conditions. Of note, the protein encoded by AKAP11 — A-kinase anchor protein 11 — interacts with glycogen synthase kinase 3b, the hypothesized target of the bipolar disorder treatment lithium.  

Moving forward, the authors note that further increasing the number of patients in future studies and more collaborative efforts will lead to the identification of biologically meaningful risk genes and pathways underlying bipolar disorder risk.

Schizophrenia studies

The paper in Nature Genetics was published at the same time as two studies published in Nature, one that used exome sequencing and a genome wide association study, that identified risk genes for schizophrenia. A press release from Rutgers University says about the three studies:

Together, these studies underscore an emerging view of schizophrenia as a breakdown in communication at the synapse and illustrate how different kinds of genetic variation affecting the same genes can influence the risk for different psychiatric and neurodevelopmental disorders.

Written by Charlotte Harrison, Science Writer

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Bipolar / Neurological / neuroscience