Press release
Monday, February 8, 2021
NIH researchers do a deep dive into the transcriptome of the brain.
A new study suggests that differences in the expression of gene transcripts (copied readings of DNA that help maintain and build our cells) may be key to understanding how mental disorders with shared genetic risk factors give place to different patterns of onset, symptoms, course of disease, and responses to treatment. The findings 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 differently in each individual,” said Francis J. McMahon, lead author of study and head of the Human Genetics Branch, which is part of the NIMH intramural research program. “We wanted to investigate why disorders present differently, despite this apparent genetic similarity.”
McMahon and colleagues suspected that the brain transcriptome might contain some clues. The human genome is made up of DNA that contains instructions to help maintain and build our cells. These instructions should be read and then copied into so-called “transcripts” so that they can be carried out. It is important to note that many different transcripts of a single gene can be copied, producing several proteins and other results. The transcriptome is the complete set of transcripts found in the body.
The researchers used postmortem tissue samples to examine the brain transcripts of 200 people who had been diagnosed with schizophrenia, bipolar disorder, major depressive disorder, or who had no known mental illness. The researchers examined both genes and transcripts expressed in the anterior subgenual cingulate cortex, a brain site involved in mood disorders, reward, impulse control, and emotion regulation. The brain tissue samples came from the NIMH Human Brain Collection Core, curated by Barbara Lipska, NIMH doctor, co-author of the work.
To increase the chances of detecting rare transcripts, the researchers sequenced the transcripts at a resolution approximately four times higher than that used in previous studies. This technique identified 1.5 times more transcripts than previous studies with the same lower-resolution method, 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 disorder and individuals without mental disorder. However, when they focused on transcripts, they found two to three times more differences between individuals in the two groups. The most notable differences arose when the researchers compared transcripts between two groups of individuals with mental disorder, for example, bipolar disorder versus schizophrenia, depression versus schizophrenia, or depression versus bipolar disorder.
“When we compared disorders in our transcription level analyzes, that’s when we saw the strong differences,” Dr. McMahon said. “Most transcripts that were expressed differently (produced at higher and lower levels) were found to be expressed in opposite directions in people with different disorders. Some transcripts were expressed in the same direction in individuals with state disorders. of spirit and in opposite sense in individuals with schizophrenia ”.
For example, different transcripts of the gene, SMARCA2, a known risk gene for autism spectrum disorder that regulates the expression of many other important genes in neuronal development, was expressed differently in brain samples from people with schizophrenia than in samples from people with the disorder. bipolar.
Parts of the instructions of a gene can be maintained or left during the transcription process. The researchers found that a common genetic variant that regulates this inclusion and exclusion, called splicing quantitative trait loci (sQTLs), may play a notable role in the inherited risk of each disorder.
“We found that subtle differences in gene expression between different disorders reflect more pronounced and specific changes in diagnosis at the transcriptional level,” McMahon said. “A cell can express many different transcripts of the same gene, resulting in different proteins and potentially different disease processes.”
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, the current study sheds light on the importance of understanding transcription level differences to gain a complete view of why mental disorders vary in onset, progression, and symptoms.
Grant: MH002810; MH002903
About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illness through basic and clinical research, paving the way for prevention, recovery and healing. For more information, visit the NIMH website.
Regarding the National Institutes of Health (NIH):
NIH, the country’s medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. NIH is the leading federal agency that conducts and supports basic, clinical, and translational medical research and investigates 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 sequencing of the transcriptome of the subgenual anterior cingulate cortex reveals changes in diagnostic and specific diagnostic RNA expression in major psychiatric disorders. Neuropsychopharmacology.