Press release
Monday, February 8, 2021
NIH researchers are doing a “deep dive” into the brain’s transcriptome.
A new study suggests that differences in the expression of genetic transcripts – copies copied from DNA that help maintain and build our cells – may hold the key to understanding how mental disorders with shared genetic risk factors lead to different patterns of onset, symptoms, disease evolution. and treatment responses. The results of the study, conducted by researchers at the National Institute of Mental Health (NIMH), which is part of the National Institute of Health, appear in the journal Neuropsihofarmacologie.
“Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, share common genetic roots, but each disorder is different in each individual,” said Francis J. McMahon, MD, lead author of the study and head of the branch. of human genetics, part of the NIMH intramural research program. “We wanted to investigate why the disorders look different, despite this apparent genetic similarity.”
McMahon and colleagues suspected that the brain 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 into the so-called “transcripts” for them to be made. Importantly, 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 postmortem tissue samples to examine the transcriptomas of the brains of 200 people who were diagnosed with either schizophrenia, bipolar disorder, major depressive disorder, or who did not have a known mental illness. The researchers examined both genes and transcripts expressed in the anterior subgenual cingulate cortex, a site of the brain involved in mood disorders, reward, impulse control, and emotion regulation. The brain tissue samples came from the NIMH Human Brain Collection Core, organized by Barbara Lipska, Dr. NIMH, lead co-author of the paper.
To increase the chances of detecting rare transcripts, the researchers sequenced the transcripts at a resolution about four times higher than that 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 takes over 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 transcripts, they found two to three times more differences between individuals in the two groups. The most visible differences occurred when the 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 transcriptional analyzes, then we saw strong differences,” said Dr. McMahon. “Most transcripts that were expressed differently – produced in higher 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 with mood disorders and in the opposite direction in people with schizophrenia. ”
For example, distinct gene transcripts, SMARCA2, a known risk gene for autism spectrum disorder that regulates the expression of many other genes important in neuronal development, have been expressed differently in brain samples from people with schizophrenia than in samples from people with bipolar disorder.
Parts of the instructions of a gene can be kept or left out of the transcription process. The researchers found that a common genetic variant that regulates this inclusion and exclusion, called quantitative trait splicing (sQTLs), can play a significant role in the inherited risk for each disorder.
We found that subtle differences in gene expression in different disorders reflect more pronounced changes and specific diagnoses in transcripts, 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 alternating time of fusion, and transcriptomic differences in certain brain regions and cell types. However, the current study highlights the importance of understanding differences at the transcriptional level 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 illness through basic and clinical research, paving the way for prevention, recovery and healing. For more information, visit the NIMH website.
About the National Institutes of Health (NIH):
NIH, the national medical research agency, includes 27 institutes and centers and is a component of the US Department of Health and Human Services. NIH is the first federal agency to conduct and support basic, clinical, and translational medical research and investigate the causes, treatments, and cures of both 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). Sequencing of the deep transcriptome of the anterior subgenual cingulate cortex reveals changes in the expression of cross-diagnostic and diagnostic-specific RNA in major psychiatric disorders. Neuropsihofarmacologie.