Determining how genetics affects mental illness could lead to new precision medicine treatments for other severe psychiatric disorders
Advanced research studies into how genetics—and a mysterious area of biological dark matter known as the “dark genome”—play a role in severe schizophrenia, could lead to personalized diagnostics and treatments for this debilitating mental illness.
Such a study conducted at the Columbia University Irving Medical Center and published in the Proceedings of the National Academy of Sciences (PNAS), titled, “High-Impact Rare Genetic Variants in Severe Schizophrenia,” may have revealed evidence of a genetic basis for severe schizophrenia.
Led by Anthony Zoghbi, MD, now Assistant Professor at Baylor College of Medicine (BCM), the Columbia University researchers examined “intolerant” genes that are not normally mutated in healthy individuals and which can have a significant impact on health when mutated. The team examined the prevalence of these mutations in individuals with schizophrenia and evaluated the impact they could have on the severity of the disease.
Rare Variant of ‘Intolerant Genes’ Identified
“The hypothesis is that these patients might have a greater prevalence of disease-causing mutations because they have such a severe form of the illness, and that’s what we ended up seeing,” Zoghbi said in a Baylor College of Medicine news release.
“Identifying rare variant risk factors in individuals with severe schizophrenia could lead to better understanding of prognosis and treatment resistance and to more opportunities for genetic counseling for families impacted by this disease. … This study also may lay the groundwork for future research on therapeutics to target genetic mutations associated with schizophrenia,” the press release noted.
The researchers focused on 112 patients with schizophrenia so severe that long-term institutionalization had been required. The team found that patients with severe schizophrenia were about twice as likely as healthy individuals to carry a rare, damaging variant of the intolerant genes they were studying.
“We think that this method of study could be a new paradigm for trying to understand how to enrich a genetic signal in a psychiatric disorder by focusing on individuals who are very severely affected by the disease,” Zoghbi explained.
His team believes their research may one day provide meaningful genetic insights that improve the diagnosis and treatment of schizophrenia. “We hope that this research brings light and attention to these patients who are often left out of cutting-edge research because of the severity of their condition.”
Exploring the Dark Genome
Researchers from Cambridge University also made an unusual discovery about the genetics underlying schizophrenia by examining the “dark genome,” areas of DNA known as biological dark matter that do not encode genes.
“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, in a University of Cambridge news release.
The researchers published their findings in Molecular Psychiatry, titled, “Novel Open Reading Frames in Human Accelerated Regions and Transposable Elements Reveal New Leads to Understand Schizophrenia and Bipolar Disorder.”
Prabakaran, the study’s senior author, was based in the University of Cambridge’s Department of Genetics when the research was performed.
“This opens up huge potential for new druggable targets,” Prabakaran continued. “It’s really exciting because nobody has ever looked beyond the genes for clues to understanding and treating these conditions before.”
The implications that areas of the genome not connected with genes can influence disease states may have tremendous implications for the future of precision medicine.
“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,” explained Chaitanya Erady, a PhD candidate in the University of Cambridge’s Department of Genetics and first author of the Molecular Psychiatry 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,” she added. “We’ve found new proteins that are involved in biological processes and are dysfunctional in disorders like schizophrenia and bipolar disorder.”
Could Doctors’ Notes Be More Valuable than Genetic Screening for Diagnosing Schizophrenia?
Though the results of the Columbia University and Cambridge University studies are positive, an earlier study conducted at Icahn School of Medicine at Mount Sinai concluded that existing genetic screening methods for schizophrenia were not any more predictive of severe schizophrenia symptoms than analysis of physicians’ notes.
In their paper published in Nature Medicine, titled, “Prognostic Value of Polygenic Risk Scores for Adults with Psychosis,” senior author Alexander W. Charney, MD, PhD, wrote, “Our results suggest that more work needs to be done to harness the potential that genetics has to improve the treatment of schizophrenia patients.”
Charney is an assistant professor in the Departments of Psychiatry and Genetics and Genomic Sciences at Icahn Mount Sinai. “The results also suggest that the detailed medical reports that doctors write may contain much more valuable and predictive information than we originally anticipated,” he added.
Nevertheless, the emerging research into how genetics affects schizophrenia, and how “intolerant” genes play a role in the severity of the disease, is certainly encouraging. Were it to lead to new precision medicine diagnostics for the condition, that would be a boon to hospitals and physicians treating this debilitating illness.
—Caleb Williams
Related Information:
High-Impact Rare Genetic Variants in Severe Schizophrenia
Identifying Rare Disease-Associated Genetic Variants in Patients with Severe Schizophrenia
Schizophrenia Study Suggests Advanced Genetic Scorecard Cannot Predict a Patient’s Fate
Prognostic Value of Polygenic Risk Scores for Adults with Psychosis