Bengaluru-based researchers have identified 42 rare mutations that influence clinical outcomes in bipolar disorder, schizophrenia and psychosis. These mutations are in the genes which are implicated in very severe mental disorders. The researchers are planning to incorporate the genes with mutations into brain cells to understand how the variants affect the working of the cells.
By sequencing the exome (the part of the genome composed of exons that gets translated into proteins) of 32 people from eight families who suffer from mental illness such as bipolar disorder, schizophrenia and psychosis, Bengaluru-based researchers have identified 42 rare mutations in the genes implicated in very severe mental disorders.
Mental illnesses such as bipolar disorder, schizophrenia and psychosis have nearly 80% chances of heritability, which indicates a genetic component. However, variations in a single gene cannot account for the manifestation of the disease. “So we adopted an approach to maximise the potential to identify the genetic components that influence the disease. This we did by studying the members of the same family who have the disease,” says Dr. Odity Mukherjee from Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bengaluru and corresponding author of a paper published in the journal Psychiatry and Clinical Neurosciences.
The variants were identified through a three-step process — the variant should cause significant perturbation to the gene, should be shared across affected members within a family, and should not be present in healthy control. Eight healthy people from five of the eight families and 25 individuals who have no history of severe mental illnesses were used as controls.
Not all the 32 people with mental illness had all the 42 variants. Each family has its own set of unique variants shared among its affected members, while also having more common variants shared across families that somehow cause similar kind of disorder, the researchers found.
“We have identified variations in the genes which we believe influences the clinical outcomes. But we are yet to understand how these variations influence the clinical outcomes,” Dr. Mukherjee says.
“The interesting part of our study is that the variants we identified are in genes that cause severe neurological disease or aberrant brain development. The variants [mutations] that cause neurological disease or aberrant brain development are not in exactly the same location in the gene that causes syndromes such as spinocerebellar ataxia and Cornelia de Lange syndrome,” says Dr. Sanjeev Jain from the Department of Psychiatry at the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru and co-author of the paper.
The fact that the identified variations overlap with genes involved in both brain development, and brain degeneration, and also in genes that have been identified in other data sets suggests that the complexity of these diseases can be slowly, but surely, unravelled, says Dr. Jain.
The researchers are planning to use induced pluripotent stem cell lines from these families and brain cells in vitro to understand how the variants affect the working of the brain cells. “This will help us understand how the genetic variants though different in each family cause similar kind of illnesses,” says Dr. Jain.
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