Press release
Monday, February 8, 2021
NIH researchers take a “deep dive” into the brain’s transcriptome.
A new study suggests that differences in the expression of gene transcripts – copied DNA readings that help maintain and build our cells – may be the key to understanding how mental disorders with shared genetic risk factors result in different patterns of onset, symptoms , disease course and responses to treatment. The results of the study, conducted by researchers at the National Institute of Mental Health (NIMH), 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 head of the Branch Human Genetics, part of the NIMH Intramural Research Program. “We wanted to investigate why the disorders appear differently, despite this apparent genetic similarity.
McMahon and his colleagues suspected that the brain’s transcriptome may contain some 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 to the so-called “transcripts” in order to be executed. It is important to note that many different transcripts can be copied from a single gene, producing a variety of proteins and other results. The transcriptome is the complete set of transcripts found in the body.
The researchers used post-mortem tissue samples to examine the brain transcriptomes of 200 people who had been diagnosed with schizophrenia, bipolar disorder, major depressive disorder or who did not have a known mental illness. The researchers examined genes and transcripts expressed in the subgenual anterior cingulate cortex, a location in the brain involved in mood disorders, reward, impulse control and regulation of emotion. The brain tissue samples came from the NIMH Human Brain Collection Core, curated by Barbara Lipska of NIMH, Ph.D., senior co-author of the article.
To increase the chances of detecting rare transcripts, the researchers sequenced the transcripts with a resolution about four times greater than that used in previous studies. This technique identified 1.5 times more transcripts than previous studies using the same method at a lower resolution, confirming that this sequencing method collects many transcripts that would otherwise have been lost.
The researchers found only modest differences in gene expression between individuals with mental disorders and individuals without mental disorders. However, when they focused on the transcripts, they found two to three times more differences between the individuals in the two groups. The most visible differences emerged when the researchers compared the transcripts between two groups of individuals with mental disorders – for example, bipolar disorder versus schizophrenia, depression versus schizophrenia, or depression versus bipolar disorder.
“When we compared the disturbances in our transcription level analyzes, that’s when we saw the marked differences,” said Dr. McMahon. “Most transcripts expressed differently – produced at higher and lower levels – ended up being expressed in opposite directions in people with different disorders. Some transcripts were expressed in the same direction in individuals with mood disorders and in the opposite direction in individuals with schizophrenia. “
For example, distinct transcripts in the gene, SMARCA2, a known risk gene for autism spectrum disorder that regulates the expression of many other important genes in neuronal development, were expressed differently in brain samples from people with schizophrenia than in samples from people with bipolar disorder.
Parts of a gene’s instructions can be kept or left out during the transcription process. The researchers found that a common genetic variant that regulates this inclusion and exclusion, called the quanti splicing trait loci (sQTLs), can play a notable role in the hereditary risk of each disease.
“We found that subtle differences in gene expression between different diseases reflect more pronounced and specific changes in diagnosis 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 disease processes.”
Further research is needed to better understand the functions of different transcripts, the alternative splicing time, and transcriptomic differences in specific brain regions and cell types. However, the current study sheds light on the importance of understanding differences in the level of transcription to get a complete picture of why mental disorders vary in onset, progression and symptoms.
Grant: MH002810; MH002903
About the National Institute of Mental Health (NIMH): NIMH’s mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH):
NIH, the country’s medical research agency, includes 27 institutes and centers and is a component of the United States Department of Health and Human Services. The NIH is the leading federal agency that conducts and supports basic, clinical and translational medical research, and is investigating the causes, treatments and cures for common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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References
Akula. N., Marenco, S., Johnson, K., Feng, N., Zhu, K., Schulmann, A., Corona, W., Jiang, X., Cross, J., England, B., Nathan, A., Detera-Wadleigh, S., Xu, Q., Auluck, PK, An, K,. Kramer, R., Apud, J., Harris, BT, Rhodes, CH, Lipska, BK, McMahon, FJ (2021). Deep transcriptome sequencing of the subgenual anterior cingulate cortex reveals changes in cross-diagnostic and diagnostic-specific RNA expression in major psychiatric disorders. Neuropsychopharmacology.