Summary: Researchers have identified new genetic clues to the biology of bipolar disorder (BD) by examining mosaic variants—mutations that arise during development and are present in only a subset of cells. Their analysis reveals an enrichment of deleterious mosaic changes in genes linked to neurodevelopmental disorders and autism spectrum disorder, along with notable heteroplasmic mutations in mitochondrial tRNA regions in people with BD.
This study highlights mosaic mutations as a previously underappreciated contributor to BD risk and suggests molecular pathways that overlap with other neurodevelopmental conditions while remaining spatially limited to particular cell populations.
Key Facts:
- The research explored the relationship between mosaic variants and bipolar disorder using deep exome sequencing.
- Participants with BD showed a higher burden of deleterious mosaic variants in genes associated with developmental disorders and autism spectrum disorder.
- The team also detected significant heteroplasmic mutations in mitochondrial tRNA genes among BD participants, including recurrent m.3243 A>G variants previously linked to mitochondrial disease.
Source: Juntendo University
Background: Bipolar disorder is a serious psychiatric condition affecting roughly 1% of the population, characterized by alternating depressive and manic episodes. Current treatments can manage symptoms but often come with side effects, incomplete response, or resistance, underscoring the need for improved, more targeted therapies. Progress toward precision medicine for BD depends on a clearer picture of its biological and genetic underpinnings.
While inherited (germline) genetic variants have been studied extensively in BD, somatic or postzygotic mosaic variants—mutations that occur during early development and are therefore not present in every cell—have received less attention. Mosaic variants can have pathogenic effects when they disrupt genes critical for brain development or cellular function, yet their contribution to psychiatric disorders remains poorly characterized.
To address this gap, a team led by Associate Professor Masaki Nishioka at Juntendo University, together with collaborators including Dr. Tadafumi Kato (Juntendo University) and Dr. Atsushi Takata (RIKEN Center for Brain Science), performed a targeted investigation of mosaic variants in BD. Their findings were published in Molecular Psychiatry on May 30, 2023.
The study analyzed DNA from peripheral blood or saliva from 235 individuals diagnosed with BD and 39 control participants without psychiatric disorders. Using deep exome sequencing (DES) at approximately 300× coverage, the researchers searched for mosaic de novo variants (mDNVs) and mitochondrial heteroplasmic variants that likely originated during early development.
Results showed a clear enrichment of deleterious mosaic variants hitting genes already implicated in developmental disorders (DD) and autism spectrum disorder (ASD). Proteins encoded by these DD/ASD genes bearing non-synonymous mosaic changes exhibited more protein-protein interactions than expected by chance, suggesting that mosaic disruption of these networks may contribute to BD pathology in a cell-specific manner.
Unexpectedly, the investigators also observed a significant excess of mitochondrial heteroplasmic variants concentrated in mitochondrial tRNA regions among BD cases. Two unrelated BD probands carried recurrent m.3243 A>G variants—well-recognized causes of mitochondrial disease—present at lower allele fractions (5–12%) than typically seen in classical mitochondrial disorders. These findings align with prior observations that mitochondrial dysfunction can be associated with psychiatric symptoms, including mood disorders and psychosis.
Both classes of deleterious mosaic variants—nuclear mDNVs affecting neurodevelopmental genes and mitochondrial tRNA heteroplasmies—were rare or absent in control participants. This pattern supports the idea that mosaic mutations in genes linked to more severe neurodevelopmental phenotypes can, when present in a subset of cells, increase susceptibility to BD without producing the full syndrome observed in germline cases.
Implications: The study expands our understanding of BD’s genetic architecture by implicating mosaic variants as contributors to disease risk. These findings encourage further investigation of mosaicism in psychiatric disorders and may help guide future precision-medicine approaches that consider both nuclear and mitochondrial mosaic variation.
Dr. Nishioka and colleagues emphasize that these results open new avenues for research into the molecular pathologies underlying neuropsychiatric conditions and could ultimately inform development of more effective, individualized treatments for BD.
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: 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 common psychiatric illness with recurrent manic and depressive episodes, affecting about 1% of people worldwide. Although genetic studies have advanced understanding of BD, its full genetic architecture and pathogenesis remain only partially resolved. In addition to germline variants, postzygotic mosaic variants have been proposed as candidate contributors to BD risk.
We applied deep exome sequencing (DES, ~300×) and validation analyses to DNA from 235 BD cases (194 trio probands and 41 single probands) and 39 controls to evaluate mosaic variants. We observed enrichment of deleterious mosaic variants in developmental disorder (DD) genes (P = 0.000552) and autism spectrum disorder (ASD) genes (P = 0.000428), including a ClinVar-registered pathogenic variant in ARID2. Proteins encoded by these DD/ASD genes with non-synonymous mosaic variants showed greater protein-protein interaction connectivity than expected, suggesting shared molecular mechanisms with DD/ASD that are limited to subsets of cells in BD.
We also detected significant enrichment of mitochondrial heteroplasmic variants in mitochondrial tRNA genes in BD (P = 0.0102). Among those, recurrent m.3243 A>G variants—known causal variants for mitochondrial disease—were identified in two unrelated BD probands at allele fractions of 5–12%, lower than typically observed in mitochondrial disease. Although peripheral tissues were used, these DES results support a possible contribution of deleterious mosaic variants in the nuclear and mitochondrial genomes to BD risk and offer new insights into the pathological roles of mosaicism in human disease.