News release
Monday, February 8, 2021
NIH researchers are taking a “deep dive” into the brain’s transcriptome.
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 with shared genetic risk factors result in different onset patterns, symptoms, disease and treatment responses. Study findings, conducted by researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appear in the journal Neuropsychopharmacology.
“Severe mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, have common genetic roots, but each disorder occurs differently in each individual,” said Francis J. McMahon, MD, a senior author of the study and chief of Human Genetics. Branch, part of the Intramural Research Program NIMH. “We wanted to investigate why disorders present differently despite this apparent genetic similarity.”
McMahon and colleagues suspected that the brain’s transcriptome may hold 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 so-called “transcripts” to execute them. Importantly, 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 post-mortem tissue samples to examine the brain transcriptomes of 200 people who had been diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, or who had no known mental illness. The researchers examined both genes and transcripts expressed in the subgenual anterior cingular 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, compiled by NIMH’s Barbara Lipska, Ph.D., co-senior author of the paper.
To increase the chances of detecting rare transcripts, the researchers sequenced the transcripts with a resolution about four times that 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 picks up many transcripts that would otherwise have been missed.
The researchers found only modest differences in gene expression between individuals with a mental disorder and those 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 versus schizophrenia, depression versus schizophrenia, or depression versus bipolar disorder.
“When we compared disorders in our transcript-level analyzes, we saw the big differences,” said Dr. McMahon. “Most transcripts expressed differently – produced at higher versus lower levels – were found to be expressed in opposite directions in people with different conditions. Some transcripts were expressed in the same direction in subjects with mood disorders and in the opposite direction in subjects 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 the development of neurons, 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 omitted during the transcription process. The researchers discovered that a common genetic variant that regulates this inclusion and exclusion, called splicing quantitative trait loci (sQTLs), can play a remarkable role in the hereditary risk for any condition.
“We found that subtle differences in gene expression between different disorders reflect more pronounced and diagnosis-specific changes at the level of transcripts,” said McMahon. “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 splicing, and the transcriptomic differences in specific brain regions and cell types. However, the current study sheds light on the importance of understanding differences at the transcript level to get a full picture of why mental disorders vary in onset, progression, and symptoms.
Grant: MH002810; MH002903
About the National Institute of Mental Health (NIMH): The 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 cure. Visit the NIMH website for more information.
About the National Institutes of Health (NIH):
NIH, the national medical research agency, includes 27 institutes and centers and is part of the United States Department of Health and Human Services. NIH is the premier federal agency that conducts and supports basic, clinical and translational medical research, investigating the causes, treatments, and cures for both common and rare diseases. To learn more 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 subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders. Neuropsychopharmacology.