17 May 2022

Predictor of mental disorders

Bipolar disorder is a severe inherited mood disorder that affects approximately 1% of the population and often begins in adulthood. Lithium preparations are the main treatment for bipolar disorder, approved half a century ago. Unfortunately, they do not help all patients and have pronounced side effects. There has been almost no progress in finding the best treatment methods during this time, partly because scientists do not fully understand how bipolar disorder occurs and how exactly lithium eliminates its symptoms.

A genetic study by the Stanley Center for Psychiatric Research at the Broad Institute of the Massachusetts Institute of Technology and Harvard University involving thousands of people suffering from bipolar disorder has shown a new understanding of the basics of this disease. The team identified variants of the AKAP11 gene as an important risk factor for both bipolar disorder and schizophrenia. The results obtained will help to understand the mechanism of action of lithium, since it is known that the AKAP-11 protein is involved in the signaling pathway that lithium targets.

The researchers collaborated with colleagues around the world as part of the Bipolar Exome Consortium to identify differences in DNA and discover those that have the greatest impact on the risk of disease. They started by comparing the exomes, or protein-coding part of the genome, of approximately 14,000 healthy volunteers and 14,000 people with bipolar disorder. People with this disease were more likely to carry gene variants that led to abnormally truncated, dysfunctional proteins. Some of these variants were in genes associated with the risk of developing schizophrenia, another severe mental illness that often begins in adolescence or at a young age.

The team then included in the analysis the results of an earlier large study by the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium involving 24,000 people with schizophrenia and compared the genome sequence of those who suffered from both of these conditions with the genome sequence of healthy volunteers. This large-scale analysis revealed rare variants of the dysfunctional AKAP11 protein that increase the risk of the disease several times, making it the strongest genetic risk factor for bipolar disorder to date.

The protein product of the AKAP11 gene interacts with another protein encoded by the GSK3B gene, which in turn is a molecular target of lithium and a potential mechanism for its effectiveness in the treatment of bipolar disorder. Thus, this discovery provides new clues about the effects of lithium on the body, which may shed light on its mechanism of action and lead to the identification of other therapeutic targets.

To study the molecular and behavioral effects of AKAP11, researchers at the Stanley Center are currently creating cellular and animal models carrying an altered form of the gene. Truncated variants effectively disable one copy of the gene in the genome, potentially reducing the amount of AKAP-11 protein by half. Models carrying similar genetic variants and characteristic protein changes are easier to create in the laboratory than models with more common disease-related variants that occur in non-coding parts of the genome and that have an unclear effect on protein function. For the first time, scientists will be able to use research models carrying genes that have been found to clearly increase the risk of bipolar disorder in humans.

The researchers are also studying whether AKAP-11 or one of its molecular partners can serve as a biomarker of this disease and help in the diagnosis or prognosis of the effectiveness of a particular therapy in individual patients.

Article by D.Palmer et al. Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia published in the journal Nature Genetics.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru according to the Broad Institute: Researchers find the first strong genetic risk factor for bipolar disorder.

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