The RNA Gene Expression in the Emergence of Psychiatric Disorders
A new study (Akula et al., 2021), which was carried out at the US National Institution of Mental Health (NIHM) and published in the journal named “Neuropsychopharmacology”, set forth that the onset of the disorder, the symptom development, and the response to treatment in psychiatric disorders with similar risk factors could be explained by the expression-based differences in the gene transcript – namely the data copied from DNA being transcribed as RNA.
Francis J. McMahon, a senior author of the study and the head of the journal, said “Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, share common genetic roots; nevertheless, each disorder manifests itself in each individual in different ways. Therefore, in this study, we wanted to research why disorders are different despite this obvious genetic similarity.”
McMahon and his counterparts thought that the transcriptome of the brain may include some hints on this matter. Transcriptome is a total set of transcripts present in the body. The human genome consists of DNA that contains instructions, which help protect and build our cells. These instructions must be read and then copied into so-called “transcripts”, which can also be named as an RNA transcript, in order for them to be applied. A number of different transcripts can be copied, and various outputs can be obtained from a single gene.
The researchers used postmortem tissue samples in order to analyze the brain transcriptomes of 200 people with no schizophrenia, bipolar disorder, major depressive disorder, or any other known psychiatric disorders. They analyzed the genes and RNA transcripts expressed in the subgenual anterior cingulate cortex, an area of the brain that is related to mood disorders, rewards, impulse control, and regulation of emotions.
The fact that the gene transcripts were analyzed in a much higher resolution is the biggest characteristic of the study, which distinguishes it from previous genetic studies. In order to increase the possibility of detecting rare transcripts, the researchers aligned the transcripts in a resolution that was approximately four times higher than those that were used in previous studies. This technique detected 1.5 times more transcripts compared to previous studies that employed the same method in a lower resolution, and it confirmed that this alignment method captured a number of transcripts that were otherwise overlooked.
When they analyzed the intergroup differences on a gene expression level, the researchers found a slight difference between individuals who have psychiatric disorders and those who don’t. Nonetheless, when they focused on the transcripts, they found two to three times more differences between the individuals in the two groups. The most striking differences occurred following the comparison of the transcripts between two groups of individuals with psychiatric disorders – e.g. bipolar disorder versus schizophrenia, depression against schizophrenia, or depression against bipolar disorder.
Dr. McMahon said “We started to see these sharp differences when we compared psychiatric disorders in our analyses on a transcript level. Emerging in various ways by being produced on higher or lower levels, many transcripts were found to be expressed in opposite ways in individuals with different disorders. For instance; the transcripts, which were expressed in the same direction in individuals with mood disorder, were expressed in the exact opposite way in individuals with schizophrenia.”
To express in a clearer manner, the different transcripts in the SMARCA2 gene (which regulates the expression of a number of genes playing an important part in neuronal development, and is also known as the risk gene for autism spectrum disorder) were observed to have been expressed in a more different way in patients with schizophrenia, compared to those with bipolar disorders.
Certain parts of a gene can be silenced or expressed during the transcription process. The research put forward that, except for specific genes, a common genetic variant, which is termed as “splicing quantitative trait loci (sQTL)” that regulates these silencing and expression processes, could be a hereditary indicator that expresses to which extent one is under risk for each disorder.
McMahon emphasized the significance of the study by saying “We found out that the subtle differences in the gene expression between different disorders reflected more apparent and diagnosis-specific changes on a transcript level. A cell can express many different transcripts from the same gene, which can result in different proteins and potentially different disorder processes.”
Consequently, further research is needed to better understand the functions of the transcripts, as well as the transcriptomic differences related to the areas of the brain. On the other hand, the current study sheds light on the importance of comprehending the differences on a transcript level in order to get a full picture of how psychiatric disorders start, progress and show symptoms in individuals.
– Distinctness of Mental Disorders Traced to Differences in Gene Readouts, Neuroscience News.
– Akula, N., Marenco, S., Johnson, K. et al. Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-020-00949-5