Examining the mosaic of mutations that contribute to bipolar disorder

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Japanese researchers have shown that genes associated with developmental disorders and autism spectrum disorders are significantly enriched with deleterious mosaic mutations in patients with bipolar disorder (BD). Similarly, the mitochondrial tRNA region of these patients also showed significant enrichment of deleterious mosaic mutations. These findings help to better understand the genetics and pathogenesis of BD. Credit: Masaki Nishioka of Juntendo University

Bipolar disorder (BD) is a serious psychiatric condition that affects approximately 1% of people. Symptoms of BD include sudden onset of depressive mood with loss of interest alternating with a manic state of hyperactivity. Patient suffering and the social cost of this disorder require the use of ongoing therapeutic management.

Current drugs, while vital for patients with B, are not perfect solutions given their potential side effects and resistance to treatment. This calls for the development of better therapies for BD, including precision medicine. A major obstacle to this process, however, lies in our limited understanding of the biological mechanisms underlying BD, i.e. its pathogenesis and the genetic architecture of people with BD.

Several studies have linked BD with inherited mutations, but recent genomic studies are now focusing on somatic mosaic variants, novel mutations that occur during developmental stages as another possible mechanism behind psychiatric disorders such as BD.

In a new study published in Molecular psychiatry a team of researchers led by associate professor Masaki Nishioka of Juntendo University, Japan, investigated the association between mosaic variants and BD risk. The research team included Dr. Tadafumi Kato, also of Juntendo University, and Dr. Atsushi Takata of the RIKEN Center for Brain Science.

“Most analyzes exploring the genetic mechanisms of BD involve extracting information from mutations shared across all patient cells. However, de novo mosaic mutations or somatic mutations, which arise during development, are not shared among all cells.We know very little about how these mutations affect diseases such as BD.Therefore, for our study, we hypothesized that de novo mosaic deleterious variants (mDNV) in genes associated with developmental disorders may play a role in the pathology of BD,” explains Dr. Nishioka.

The team recruited 235 participants with BD and 39 control participants without psychiatric disorders. They collected blood or saliva samples from participants and analyzed DNA extracted from these samples using deep exome sequencing (DES) to detect mosaic variants that originated during early development.

Participants with BD had mosaic variants enriched in genes responsible for causing developmental disorders (DD) and autism spectrum disorders (ASD). Furthermore, proteins encoded by DD/ASD genes with mosaic variant proteins were closely linked and had more protein-protein interactions than expected.

Surprisingly, the team also found significant heteroplasmic mutations (another class of mosaic variants) in the mitochondrial tRNA genes of participants with BD. For reference, some tRNA mutations are known to be pathogenic for other diseases.

Indeed, two participants with mitochondrial tRNA mutations had recurrent m.3243 A > G variants, known to be the main causative variants of mitochondrial diseases, MELAS, which is a severe neurodevelopmental disorder. This finding complements other studies that have found that patients with mitochondrial diseases often exhibit symptoms of bipolar disorder or schizophrenia.

Furthermore, both sets of mDNV deleterious mosaic variants and mitochondrial tRNA variants were absent or rarely observed in control participants. These results indicate that the molecular mechanisms underlying DD/ASD might also contribute to BD in an impaired manner through mosaic mutations. Furthermore, they suggest that mitochondrial tRNA variants might be associated with BD despite the patient showing no overt symptoms of mitochondrial diseases.

With this study, the researchers demonstrate that mosaic mutations, particularly those in neurodevelopmental disorder genes and mitochondrial tRNA genes, may be involved in the pathophysiology of BD. Dr. Nishioka is encouraged by the significance of their study findings for scientists pursuing research into the molecular pathologies in neuropsychiatric diseases.

He concludes: “Our research sheds new light on the genetic architecture of BD and provides more insight into the pathological contribution of mosaic variants in human disease. This could potentially pave the way and accelerate new research for the development of more effective drugs and precision for treatment of BD and other psychiatric disorders”.

More information:
Masaki Nishioka et al, Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder, Molecular psychiatry (2023). DOI: 10.1038/s41380-023-02096-x

About the magazine:
Molecular psychiatry

Provided by Juntendo University Research Promotion Center

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