Variations in certain genes put people at risk of developing certain psychiatric disorders. But what’s really important to understand is that genes alone don’t tell the whole story. Every cell in our entire body contains the same DNA, but how that DNA is expressed — in the form of RNA and proteins, through the processes of translation and transcription — is what makes all the difference in the world. Looking at the RNA, which is a product of DNA being read and transcribed, gives us information about the expression level of different genes — thus increasing our understanding of the modified molecular machinery of the disorders. This would open several doors for therapeutic approaches in psychiatry!

Researchers from the University of California (Gandal et. al, 2018) analysed the brains of deceased individuals who suffered from autism, schizophrenia, depression, bipolar disorder and alcoholism, and those that has not been diagnosed with any psychiatric illness. They studied the expression level of these genes by studying the DNA microarray, which consists of the determining the expression level of several genes (DNA expression is the process by which instructions in DNA are converted into a product, such as a RNA or protein).

They studied the DNA microarray in the cerebral cortex of 700 brains from subjects with autism spectrum disorder (henceforth referred to as autism)(n=50 subjects’ brains), schizophrenia (n=159), bipolar disorder (n=94), depression (n=87), alcoholism (n=17), and matched controls (n=293). Inflammatory bowel disease (n=197) was included as a non-neural comparison.

Results: Gene expression patterns overlap

They compared the transcriptome of cerebral cortical neurons in the 700 brains and checked for similarities between the expression level of certain genes in the cerebral cortex of people with Autism, Schizophrenia, Bipolar Disorder and Major Depression. A transcriptome is the sum total of all the messenger RNA molecules expressed from the genes. They examined 13 groups of genes that are thought to function together.

The analysis reveals that certain psychiatric disorders, although not similar symptomatically, have overlap at the level of gene expression. For instance, bipolar disorder is often considered a mood disorder and is thought to be similar to depression. One would then assume that the underlying biological characteristics would also be similar, but the analysis indicates that gene activity in bipolar disorder is in fact most similar to schizophrenia, and not depression. In addition, Gandal et. al also found little to no correlation between gene expression in alcoholism and the other four psychiatric disorders.

The results also demonstrated that certain genes in the cerebral cortex are active in both autism and schizophrenia, but they are far more active in autism. Indeed, this could mean that over-expression of these genes could play a role in the manifestation of autism’s symptoms. On the other hand, genes thought to be important for neuronal firing were under-active in autism, schizophrenia and bipolar disorder. This would suggest that perhaps the change in communication between neurons has an important role to play in the development and/or manifestation of all three conditions.

Electrically active neurons weren’t the only types of cells studied in this brilliant project. They also studied other types of neurons, namely astrocytes and microglia. Astrocytes, a type of glial cell, are abundant in the brain, and are associated with synapses and serve several functions, one of which is to regulate neuronal transmission. Microglia, also a type of glial cell, are part of the brain’s immune system and protect it against inflammation.

The results of this study showed some genes that were over-expressed in microglia specifically in autism. Since autism is an early onset disorder, these results indicate that microglia play an important role in neurodevelopment. These findings have led to the launch of a clinical trial to see if a certain antibiotic can keep the activity of these microglia in check. Bipolar disorder and schizophrenia and autism are all similar in astrocyte up-regulation, but bipolar disorder and schizophrenia have a more similar signature.

Interestingly, major depression did not display over- or under-expression for any of the genes for which the three other disorders have an up- or down-regulation signature.

This is indeed a really big step in understanding the aetiology of these disorders. Moreover, it could also change our perspective of how we view them — as independent disorders with distinct symptomatology or as a subset of symptoms under a larger, mental illness umbrella. Given that a lot of mental disorders often present with co-morbidities (disorders that present together), the latter way might end up being the way we look at them soon. However, while the authors (and us) are excited by these findings related to genetics, they’re fully aware that environmental factors also have a huge contribution. In addition, the mechanism for the observed hyper- or under-activity remains to be studied and understood, and once scientists are able to do that, they might be able to change the outcome.

Furthermore, to remove the possibility that the gene expression changes weren’t in fact caused by the anti-psychotics that these patients could possibly have been on, they did another step of analysis. They compared the samples of their subjects to samples from non-human primates. The researchers first induced psychosis in these primates by administering PCP (popularly known as angel dust) and then giving them antipsychotics. What they observed was that antipsychotics actually partially normalised the alterations in activity.

“Gene-expression patterns might someday be good targets for reversal by medication,” Geschwind said. “In [our study] the drugs at least partially normalised gene expression in the brain.”

Implications

Daniel Geschwind, one of the authors of the paper and the director of the UCLA Center for Autism Research and Treatment, says:

“We’re on the threshold to using genomics and molecular technology to look at [mental illness] in a way we’ve never been able to do before. Psychiatric disorders have no obvious pathology in the brain, but now we have the genomic tools to ask what actually goes awry in these brains. These findings provide a molecular, pathological signature of these disorders, which is a large step forward. The major challenge now is to understand how these changes arose.”

The hypothesis is that these observed changes in gene expression probably lead to some form of confused communication in the brain. It then becomes important to understand how gene expression can cause these changes and confusion and aim to target that therapeutically.

Back to the drawing board — we can also use these molecular signatures to better define these diseases.

The future of psychiatric medicine looks a little brighter.

Source: Gandal et al., Science 359, 693–697 (2018)