Gene Expression Differences Could Explain Symptoms of Different Mental Disorders

Schizophrenia

Differences in gene expression could help explain why major mental disorders that have similar genetic roots produce such different symptoms in those affected, suggest results from the National Institute of Mental Health in Bethesda.

The researchers found that although people with conditions such as schizophrenia, bipolar disorder, and major depressive disorder often have mutations in the same genes, differential transcriptional expression through mechanisms such as alternative splicing leads to diverse physiological outcomes.

“When we compared disorders in our transcript-level analyses, that is when we saw the stark differences,” said Francis McMahon, M.D., chief of the Human Genetics Branch at the National Institute of Mental Health, who led the study.

“Most transcripts that were expressed differently – produced in higher versus lower levels – turned out to be expressed in opposite directions in people with different disorders. Some transcripts were expressed in the same direction in individuals with mood disorders and the opposite direction in individuals with schizophrenia.”

McMahon and colleagues analyzed 200 postmortem brain tissue samples donated by people who had a diagnosis of schizophrenia, bipolar disorder, major depressive disorder, or who did not have a known mental illness. The samples were from the subgenual anterior cingulate cortex area of the brain, which is known to be involved in emotional regulation, impulse control and mood disorders.

The team tested the samples for genetic variation and also looked at transcripts to assess how different genes were being expressed.

“Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, share common genetic roots, but each disorder presents differently in each individual,” said McMahon. “We wanted to investigate why disorders present differently, despite this seeming genetic similarity.”

As described in the journal Neuropsychopharmacology, the researchers carried out deep RNA sequencing (at a much more in-depth level than carried out in most studies) and evaluated over 85,000 gene transcripts. By using this method, they managed to identify around 250 transcripts that were differentially expressed in different disorders. The transcripts came from a variety of genes, but particularly those involved in neurological functions.

Differences between controls and people with different disorders were much more pronounced on the transcript level rather than by comparing genetic variation alone.

The research team identified many common genetic variants that had previously been linked to one or more psychiatric disorders. However, the transcripts of these genes were frequently subject to alternative splicing with similar transcripts linked to specific disorders.

“We found that subtle differences in gene expression across different disorders reflect more pronounced and diagnosis-specific changes at the level of transcripts,” said McMahon.

“A cell can express many different transcripts from the same gene, resulting in different proteins – and potentially different illness processes.”

McMahon and colleagues concede that their study was small and that the transcripts they sequenced from the brain samples could have been influenced by postmortem changes in the tissue. They want to do more research to understand what triggers the formation of these alternative transcripts and when. They also want to understand more about the impact of external forces such as medication and other environmental factors.

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