Bipolar disorder (BD) is thought to impact nearly one percent of all people. BD can cause a cycle of sudden, depressed moods and manic, hyperactive states. The current treatments for BD come with side effects and don't help all patients. One major problem with treating BD, like other psychiatric disorders, is that we still have only a limited understanding of the causes. Genetic factors are thought to have an influence on the risk of BD. New work reported in Molecular Psychiatry has focused on somatic mosaic variants, which are mutations that arise in genes after birth, so they may only be found in subsets or populations of cells.
Studies that have investigated the possible genetic causes underlying BD have focused on the genome that all cells in the body carry. But new mutations that occur during development will not be found in all cells. Study leader Professor Masaki Nishioka of Juntendo University, noted that we don't know much about how these somatic or de novo mutations are involved in disorders such as BD.
In this study, the scientists focused on deleterious mosaic de novo variants (mDNVs) that are found in genes linked to developmental disorders. They collected blood or saliva from 235 BD patients and 39 unaffected individuals, and extracted DNA. Deep exome sequencing (DES) was then applied to reveal mosaic variants that arose in early development. In deep sequencing, the same regions of DNA are sequenced many times to find any variations in those sequences that might be found in different cells. Exome sequencing solely sequences the protein-coding portions of the genome.
This revealed that BD patients had more mosaic variants in genes that have been linked to developmental and autism spectrum disorders. Proteins that are encoded by these genes were often closely connected, with many interactions. These variants were absent or rare in controls.
The investigators were also surprised to find high levels of a type of mosaic variant called heteroplasmic mutations in the mitochondrial tRNA of BD patients, in which more than one mitochondrial DNA variant is found in a single cell.
There were two study participants who carried the same mitochondrial tRNA mutations, which have also been found to cause a severe neurodevelopmental disorder called MELAS. This work supports previous studies showing that mitochondrial disease patients often have bipolar disorder or schizophrenia symptoms.
The study indicated that mosaic mutations could be important to BD risk or development, especially when those mutations arise in neurodevelopmental disorder genes and mitochondrial tRNA genes.
"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," said Nishioka.