News Release
Monday 8 February 2021
NIH researchers take ‘deep dive’ into the transcriptome of the brain.
A new study suggests that differences in the expression of gene transcripts – readings copied from DNA that help maintain and build our cells – may be key to understanding how mental disorders have shared genetic risk factors different patterns of onset, symptoms, course of disease, and treatment responses. Findings from the study, conducted by researchers from the National Institutes 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 depressive disorder, have common genetic roots, but each disorder shows up differently in each individual,” said Francis J. McMahon, MD, a senior author of the study and head of the study. Human Genetics Branch, part of the in-house research program NIMH. “We wanted to investigate why abnormalities occur differently, despite this genetic similarity.”
McMahon and colleagues suspected that the transcriptome of the brain might contain some clues. The human genome is made up of DNA that contains instructions for maintaining and building our cells. These instructions should be read and then copied into so-called ‘transcripts’ to execute them. It is important that many different transcripts can be copied from a single gene, yielding a variety of proteins and other outputs. 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 with schizophrenia, bipolar disorder, major depression or who did not have a known mental illness. The researchers examined both genes and transcripts expressed in the subgenual anterior cingular cortex, a brainstem involved in mood disorders, reward, impulse control and emotion regulation. The brain tissue samples are from the NIMH Human Brain Collection Core, compiled by NIMH’s Barbara Lipska, Ph.D., co-senior author of the article.
To increase the chance 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 absorbs many transcripts that would otherwise be missed.
The researchers found only modest differences in gene expression between individuals with a mental disorder and individuals 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 striking differences emerged when the researchers compared 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 disorders in our transcriptional level analyzes, we saw the strong differences,” said Dr. McMahon said. ‘Most transcripts expressed differently – produced in higher and lower levels – appear to be expressed in opposite directions in people with different disorders. Some transcripts have been pronounced in the same direction in individuals with mood disorders and the opposite direction in individuals with schizophrenia. ”
For example, different transcripts in the gene, SMARCA2, a known risk gene for autism spectrum disorder that regulates the expression of many other genes important in neuronal development, is expressed differently in brain samples from people with schizophrenia than in samples from people with bipolar disorder.
Portions of the instructions of a gene can be left in or out of account 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 significant role in the hereditary risk for each disorder.
“We found that subtle differences in gene expression between different disorders reflected more pronounced and diagnosis-specific changes at the level of transcripts,” McMahon said. “A cell can express many different transcripts of the same gene, resulting in different proteins and possibly different disease processes.”
More research is needed to better understand the functions of different transcripts, the timing of alternative cleavage, and the transcriptomic differences in specific brain regions and cell types. However, the present study sheds light on the importance of understanding differences at the transcriptional level to gain a complete picture 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 cure. Visit the NIMH website for more information.
About the National Institutes of Health (NIH):
NIH, the country’s medical research agency, contains 27 institutes and centers and is part of the U.S. Department of Health and Human Services. NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, investigating the causes, treatments, and drugs for common and rare diseases. Visit www.nih.gov for more information on NIH and its programs.
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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 subgenual anterior cingular cortex reveals cross-diagnostic and diagnostic-specific RNA expression changes in major psychiatric disorders. Neuropsychopharmacology.