Mosaic Mutations Reveal New Insights into Bipolar Disorder

Summary: Researchers unearthed new understandings about the genetic mechanisms behind bipolar disorder (BD).

The team focused on mosaic variants – new mutations occurring during developmental stages. They discovered that participants with BD possessed mosaic variants enriched in genes related to developmental disorders and autism spectrum disorder.

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

Key Facts:

Source: Juntendo University

Bipolar disorder (BD) is a major psychiatric condition that afflicts about 1% of people. Symptoms of BD include sudden onset of depressive mood with loss of interest which alternates with a manic state of hyperactivity.

The suffering of the patients and societal cost of this disorder requires the use of continued therapeutic management. Current medications—although vital for patients with BD—are not perfect solutions, given their potential side-effects and treatment resistance. This necessitates the development of better therapeutics for BD, including precision medicine.

A major hindrance to this process, however, lies in our limited understanding of the underlying biological mechanisms of BD, i.e., its pathogenesis and the genetic architecture of people with BD.

Several studies have linked BD with hereditary mutations, but recent genomic studies are now focusing on somatic mosaic variants—new mutations occurring during developmental stages—as another possible mechanism behind psychiatric disorders like BD.

In a new study published in Molecular Psychiatry on May 30, 2023, a team of researchers led by Associate Professor Masaki Nishioka of Juntendo University, Japan, investigated the association between mosaic variants and the risk of BD. The research team included Dr. Tadafumi Kato, also from Juntendo University, and Dr. Atsushi Takata from RIKEN Center for Brain Science.

"Most analyses exploring the genetic mechanisms of BD involve extracting information from mutations that are shared among all the cells of the patients. However, mosaic de novo mutations or somatic mutations, which arise during development, are not shared among all the cells.

"We know very little about how these mutations influence diseases like BD. Therefore, for our study, we hypothesized that deleterious mosaic de novo variants (mDNVs) in the genes associated with developmental disorders may have a role in BD's 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 the participants and analyzed the 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 that are responsible for causing developmental disorders (DD) and autism spectrum disorder (ASD). Moreover, the proteins encoded by the DD/ASD genes with the proteins of the mosaic variants 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 mitochondrial tRNA genes of participants with BD. For reference, some tRNA mutations are known to be pathogenic for other diseases.

In fact, two participants with mitochondrial tRNA mutations had recurrent m.3243 A > G variants, which are known to be major causal variants for mitochondrial diseases, MELAS, which is a serious 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 the sets of deleterious mosaic variants—mDNVs and mitochondrial tRNA variants—were either absent or rarely observed in the control participants. These results indicate that the molecular mechanisms underlying DD/ASD could also contribute to BD in a compromised way through mosaic mutations.

Moreover, they suggest that mitochondrial tRNA variants could be associated with BD despite the patient showing no obvious 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 what their study's findings mean for scientists pursuing the research of molecular pathologies in neuropsychiatric diseases.

He concludes, "Our research sheds new light on the genetic architecture of BD and provides more insights into the pathological contribution of mosaic variants in human diseases.

"This could potentially pave the way and expedite new research for the development of more effective, precision medications for treating BD and other psychiatric disorders."

Author: Yoshitaka NakashimaSource: Juntendo UniversityContact: Yoshitaka Nakashima – Juntendo UniversityImage: The image is credited to Neuroscience News

Original Research: Open 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

Abstract

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 issue, afflicting around 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. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD.

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

We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428).

The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted 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.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5–12%, lower than in mitochondrial diseases.

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

These results, 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.

So interesting the findings I had a son born in 1966 the thyroid was deficient he was assessed as mentally impaired and put in kew cottages australia. went to children's hospital he was nearly 3 he was put on thyroid tablets and growth tablets and was in work shops keep complaining he was stressed then he got schizophrenia there is many people like him that get schizophrenia I think they are under a lot of pressure to be like normal he died at 49 he smoked too much and the drink he didn't care if he died that's why I like reading your findings.he lived at home and his girlfriend.it's all the weird things in their head that's why they struggle

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