Mosaic Mutations Reveal New Insights About Bipolar Disorder – Neuroscience News

Summary: Researchers have unearthed new insights into the genetic mechanisms underlying bipolar disorder (BD).

The team focused on mosaic variants – new mutations that occur during developmental stages. They found that participants with BD possessed enriched mosaic variants of genes related to developmental disorders and autism spectrum disorders.

In addition, significant heteroplasmic mutations in mitochondrial tRNA genes were found in BD participants.

Main aspects:

  1. Researchers have conducted a new study to investigate the link between mosaic variants and the risk of bipolar disorder (BD).
  2. The study found that BD patients carried enriched mosaic variants of genes associated with developmental disorders and autism spectrum disorders.
  3. The team also identified significant heteroplasmic mutations in mitochondrial tRNA genes in participants with BD.

Source: 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 inMolecular psychiatryOn May 30, 2023, 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, mosaicde novomutations or somatic mutations, which arise during development, are not shared among all cells.

“We know very little about how these mutations affect diseases like BD. Therefore, for our study, we hypothesized that deleterious mosaicde novovariants (mDNVs) in genes associated with developmental disorders may play a role in BD pathology,” 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 and precision medicines for the treatment of BD and other psychiatric disorders.

About this genetics and bipolar disorder research news

Author: Yoshitaka Nakashima
Source: Juntendo University
Contact: Yoshitaka Nakashima – Juntendo University
Image: The image is credited to Neuroscience News

Original research: Free access.
“Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder” by Masaki Nishioka et al. Molecular psychiatry


Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder

Bipolar disorder (BD) is a global medical problem, afflicting approximately 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. In addition to germline variants, postzygotic mosaic variants are proposed as novel candidate mechanisms contributing to BD.

Here, we performed large deep exome sequencing (DES, ~300) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 trio probands and 41 single cases) and 39 controls.

We found enrichment of developmental disorder (DD) genes in genes affected by mosaic deleterious variants in BD (P=0.000552), including a pathogenic variant registered in ClinVarARIDE2. An enrichment of mosaic variants deleterious to autism spectrum disorder (ASD) genes has also been observed (P=0.000428).

Proteins encoded by DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interactions than expected, suggesting molecular mechanisms shared with DD/ASD but limited to a subset of cells in BD.

We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P=0.0102).

Among them, recurrent m.3243A>G variants known to be causative for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 512%, lower than in mitochondrial diseases.

Despite the limitation of the use of peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for more severe phenotypes, such as DD/ASD, to BD risk and further demonstrates that the same paradigm can be applied to the mitochondrial genome.

These findings, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

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