Differences in gene readings may shed light on mental illness

A new study shows how differences in gene transcript expression (reads copied from DNA that help maintain and build cells) lead to different patterns of development, symptoms, and course of psychiatric disorders that share genetic risk factors. Diseases, and therapeutic responses, suggest that they may hold the key to understanding what they bring.

The results of studies conducted by researchers at the National Institute of Mental Health (NIMH), which is part of the National Institute of Health, are published in the journal. Neuropsychopharmacology..

“Major psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder share a common genetic root, but each disorder manifests itself differently in each individual,” said a senior researcher. The Department of Human Genetics, the author and part of the on-campus research program NIMH. “I wanted to investigate why the disorder appears differently despite the genetic similarities that look like this.”

McMahon et al. Suspected that the transcriptome of the brain might have some clues. The human genome is made up of DNA that contains instructions to help maintain and build cells. To read these instructions and then execute them, you need to copy them into a so-called “transcript”. Importantly, many different transcripts can be copied from a single gene to produce different proteins and other outputs. The transcriptome is the complete set of transcriptomes found in the body.

Using postmortem tissue samples, researchers used 200 brain transcriptomes diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, or without known psychiatric disorders. I looked it up.

Researchers examined both genes and transcripts expressed in the anterior cingulate cortex, the brain region involved in mood disorders, rewards, impulsivity, and emotional regulation. Brain tissue samples are NIMH co-authors Barbara Lipska, Ph.D. Obtained from the NIMH Human Brain Collection Core curated by.

To increase the likelihood of detecting rare transcripts, researchers sequenced the transcripts at a resolution approximately four times the resolution used in previous studies. This technique identifies 1.5 times more transcripts than previous studies using the same method at low resolution, and this sequencing technique detects many transcripts that would otherwise have been missed. Was confirmed.

Researchers have seen only slight differences in gene expression between individuals with and without mental illness. However, when they focused on transcripts, they found a 2-3x difference between the two groups of individuals.

The most striking differences appeared when researchers compared transcripts between two groups of individuals with mental illness-for example, bipolar disorder and schizophrenia, depression and schizophrenia, or depression. Disease and bipolar disorder.

“When we compared obstacles in a transcript-level analysis, that was when we saw a significant difference,” said Dr. McMahon. “Most transcripts of different expression (produced at high and low levels) were found to be expressed in opposite directions in people with different disorders. Some transcripts were found in individuals with mood disorders. It was expressed in the same direction and in the opposite direction in individuals with schizophrenia. “

For example, different transcripts of the gene SMARCA2, a known risk gene for autism spectrum disorders that regulate the expression of many other genes important for neurogenesis, are found in brain samples of people with schizophrenia and in bipolar disorder. It was expressed differently in people’s samples. ..

Some of the genetic directives may be retained or omitted during the transcription process. Researchers say that a common genetic variation that regulates inclusion and exclusion, called the splicing quantitative trait locus (sQTL), may play a remarkable role in the genetic risk of each disorder. I found.

Subtle differences in gene expression between different disorders were found to reflect more pronounced and diagnostic-specific changes at the transcript level. Cells can express many different transcripts from the same gene, resulting in different proteins and potentially different disease processes. “

Francis J. McMahon, MD, National Institute of Mental Health, Principal Research Author and Director of Human Genetics

More research is needed to better understand the function of different transcripts, the timing of alternative splicing, and the differences in transcriptomes in specific brain regions and cell types. However, current research highlights the importance of understanding differences in transcriptional levels in order to fully understand why the onset, progression, and symptoms of mental illness are different.