Differences in gene readings may shed light on mental disorders

A new study suggests that differences in the expression of genetic transcripts – reads copied from DNA that help maintain and build our cells – may hold the key to understanding how mental disorders with shared genetic risk factors cause different patterns of onset, symptoms, disease progression and responses to treatment.

The results of the study, conducted by researchers at the National Institute of Mental Health (NIMH), which is part of the National Institutes of Health, appear in the journal Neuropsychopharmacology.

“Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, share common genetic roots, but each disorder presents itself differently in each individual,” said Francis J. McMahon, MD, senior author of the study and study leader. Department of Human Genetics, part of the intramural research program NIMH. “We wanted to investigate why the disorders present themselves differently, despite this apparent genetic similarity.”

McMahon and his colleagues suspected that the brain transcriptome might contain clues. The human genome is made up of DNA that contains instructions to help maintain and build our cells. These instructions must be read and then copied into “transcripts” for them to be executed. It is important to note that many different transcripts can be copied from a single gene, giving a variety of proteins and other outputs. The transcriptome is the complete set of transcriptions found in the body.

The researchers used postmortem tissue samples to examine brain transcriptomes from 200 people who had been diagnosed with schizophrenia, bipolar disorder, major depressive disorder, or who had no known mental illness.

Researchers looked at both genes and transcripts expressed in the anterior subgenital cingulate cortex, a brain site involved in mood disorders, reward, impulse control, and emotion regulation. Brain tissue samples were from the NIMH Human Brain Collection Core, organized by Barbara Lipska, Ph.D., co-lead author of the article.

To increase the chances of detecting rare transcripts, the researchers sequenced the transcripts at a resolution approximately four times the resolution used in previous studies. This technique identified 1.5 times more transcripts than previous studies using the same method at lower resolution, confirming that this sequencing method collects many transcripts that would otherwise have been missed.

The researchers found only modest differences in gene expression between people with a mental disorder and people without a mental disorder. However, when they focused on the transcripts, they found two to three times as many differences between individuals in the two groups.

The most noticeable differences arose when researchers compared the transcripts between two groups of individuals with a mental disorder – for example, bipolar disorder versus schizophrenia, depression versus schizophrenia, or depression versus bipolar disorder.

“When we compared the disorders in our transcript-level analyzes, that’s when we saw the marked differences,” said Dr. McMahon. Most of the differently expressed transcripts – produced at higher levels versus lower levels – were found to be expressed in opposite directions in people with different disorders. Some transcripts were expressed in the same direction in people. suffering from mood disorders and in the opposite direction in people with schizophrenia. “

For example, distinct transcripts of the SMARCA2 gene, a known risk gene for autism spectrum disorder that regulates the expression of many other genes important in neural development, have been expressed differently in brain samples from people with schizophrenia. than in samples from people with bipolar disorder. .

Parts of a gene’s instructions may be retained or omitted during the transcription process. Researchers have found that a common genetic variant that regulates this inclusion and exclusion, called quantitative splice trait loci (sQTL), may play a notable role in the inherited risk of each disorder.

We have found that subtle differences in gene expression between different disorders reflect more pronounced and diagnostic-specific changes in transcripts. A cell can express many different transcripts from the same gene, resulting in different proteins – and potentially different disease processes. “

Francis J. McMahon, MD, senior study author and head of the division of human genetics, National Institute of Mental Health

More research is needed to better understand the functions of different transcripts, the timing of alternative splicing, and transcriptomic differences in specific brain regions and cell types. However, this study highlights the importance of understanding the differences in transcripts to get a complete idea of ​​why mental disorders vary in appearance, progression, and symptoms.