Dark Genome Region May Provide Bipolar Disorder, Schizophrenia Drug Targets

Adult woman with split personality
Credit: Iuliia Isaieva/Getty Images

Researchers investigating the DNA outside our genes (the “dark genome”)  report that they have discovered recently evolved regions that code for proteins associated with schizophrenia and bipolar disorder. They say these new proteins can be used as biological indicators to distinguish between the two conditions, and to identify patients more prone to psychosis or suicide.

Schizophrenia and bipolar disorder are hard to diagnose and treat. Despite being among the most heritable mental health disorders, few clues to their cause have been found in genes.

The scientists think that hotspots in the dark genome associated with the disorders may have evolved because they have beneficial functions in human development, but their disruption by environmental factors leads to susceptibility to, or development of, schizophrenia or bipolar disorder. The team’s results (“Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder”) are published in Molecular Psychiatry.

Schizophrenia (SCZ) and bipolar disorder are debilitating neuropsychiatric disorders arising from a combination of environmental and genetic factors. Novel open reading frames (nORFs) are genomic loci that give rise to previously uncharacterized transcripts and protein products. In our previous work, we have shown that nORFs can be biologically regulated and that they may play a role in cancer and rare diseases. More importantly, we have shown that nORFs may emerge in accelerated regions of the genome giving rise to species-specific functions,” write the investigators.

“We hypothesize that nORFs represent a potentially important group of biological factors that may contribute to SCZ and bipolar disorder pathophysiology. Human accelerated regions (HARs) are genomic features showing human-lineage-specific rapid evolution that may be involved in biological regulation and have additionally been found to associate with SCZ genes. Transposable elements (TEs) are another set of genomic features that have been shown to regulate gene expression.

“As with HARs, their relevance to SCZ has also been suggested. Here, nORFs are investigated in the context of HARs and TEs. This work shows that nORFs whose expression is disrupted in SCZ and bipolar disorder are in close proximity to HARs and TEs and that some of them are significantly associated with SCZ and bipolar disorder genomic hotspots. We also show that nORF encoded proteins can form structures and potentially constitute novel drug targets.”

“By scanning through the entire genome we’ve found regions, not classed as genes in the traditional sense, which create proteins that appear to be associated with schizophrenia and bipolar disorder,” said Sudhakaran Prabakaran, PhD, who was based in the University of Cambridge’s department of genetics when he conducted the research, and is senior author of the report.

“This opens up huge potential for new druggable targets. It’s really exciting because nobody has ever looked beyond the genes for clues to understanding and treating these conditions before.”

Human-specific genomic components

The researchers think that these genomic components of schizophrenia and bipolar disorder are specific to humans—the newly discovered regions are not found in the genomes of other vertebrates. It is likely that the regions evolved quickly in humans as our cognitive abilities developed, according to the researchers, who note that they are easily disrupted, resulting in the two conditions.

“The traditional definition of a gene is too conservative, and it has diverted scientists away from exploring the function of the rest of the genome,” said Chaitanya Erady, a PhD student and researcher in the University of Cambridge’s department of genetics and first author of the study.

“When we look outside the regions of DNA classed as genes, we see that the entire human genome has the ability to make proteins, not just the genes. We’ve found new proteins that are involved in biological processes and are dysfunctional in disorders like schizophrenia and bipolar disorder.”

The majority of currently available drugs are designed to target proteins coded by genes. The new finding helps to explain why schizophrenia and bipolar disorder are heritable conditions, and could provide new targets for future treatments.

Prabakaran left his University position earlier this year to create the company NonExomics, to commercialize this and other discoveries. Cambridge Enterprise, the commercialization arm of the University of Cambridge, has assisted NonExomics by licensing the intellectual property. Prabakaran has raised seed funding to develop new therapeutics that will target the proteins implicated in schizophrenia and bipolar disorder, and other diseases.

His team has now discovered 248,000 regions of DNA outside of the regions conventionally defined as genes, which code for new proteins that are disrupted in disease.

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