Bipolar disorder (BD) is a significant psychiatric condition that affects approximately 1% of the population. It is characterized by alternating episodes of depressive moods and manic states of hyperactivity.
Managing this disorder is crucial, as it causes distress to patients and carries a societal cost. While current medications are important, they have drawbacks such as side effects and treatment resistance. Hence, there is a need for better therapeutics, including precision medicine, to address BD. However, our understanding of the biological mechanisms underlying BD, including its causes and genetic aspects, remains limited. While previous studies have linked BD with hereditary mutations, recent research is exploring somatic mosaic variants—new mutations occurring during development—as another potential mechanism for psychiatric disorders like BD.
A new study led by Associate Professor Masaki Nishioka from Juntendo University, Japan, and published in Molecular Psychiatry on May 30, 2023, investigated the connection between mosaic variants and the risk of BD. The research team, including Dr. Tadafumi Kato from Juntendo University and Dr. Atsushi Takata from RIKEN Center for Brain Science, focused on deleterious mosaic de novo variants (mDNVs) in genes associated with developmental disorders. These mosaic variants, unlike mutations shared by all cells, arise during early development and may influence the pathology of BD.
The study involved 235 participants with BD and 39 control participants without psychiatric disorders. Blood or saliva samples were collected, and DNA extracted from these samples was analyzed using deep exome sequencing (DES) to detect mosaic variants. Participants with BD had mosaic variants enriched in genes responsible for developmental disorders (DD) and autism spectrum disorder (ASD). Additionally, the proteins encoded by these genes showed significant interactions with proteins from the mosaic variants.
Surprisingly, the team also discovered heteroplasmic mutations in mitochondrial tRNA genes among participants with BD. Some tRNA mutations are known to be pathogenic for other diseases. In fact, two participants had recurrent m.3243 A > G variants associated with mitochondrial diseases, including MELAS, a severe neurodevelopmental disorder. This finding aligns with previous studies showing that patients with mitochondrial diseases often exhibit symptoms of bipolar disorder or schizophrenia.
Moreover, these deleterious mosaic variants were either absent or rare in the control group, suggesting their potential contribution to BD. The study indicates that mosaic mutations, particularly those in neurodevelopmental disorder genes and mitochondrial tRNA genes, may play a role in the pathophysiology of BD. These findings offer new insights into the genetic architecture of BD and the impact of mosaic variants on human diseases. The research has the potential to facilitate the development of more effective, precise medications for treating BD and other psychiatric disorders.
