Creating an effective treatment for schizophrenia requires a better understanding of its biology, of the genes that cause it. Using technology to illuminate chromosomes, scientists confirmed the underlying genetics of this mental disorder. The identified genetic disruptions occur at a crucial time in brain development.
The science team hopes its research, published Wednesday in the journal Nature, leads to new medications to treat the disorder.
More important, using a similar strategy could help researchers identify genes that lead to autism and other brain disorders, said Dr. Daniel Geschwind, principal investigator and a professor of neurology and psychiatry at the University of California, Los Angeles School of Medicine.
Building on previous research
Schizophrenia is a chronic, severe and disabling mental disorder. Its symptoms may include delusions, thought disorder and hallucinations. Worldwide, schizophrenia affects 50 million people, many unable to function normally, as they are tormented with delusions and hallucinations. No cure exists, so doctors try to manage the symptoms with medications and therapy.
Importantly, schizophrenia often runs in families, so scientists have long believed it is a genetic disorder.
A 2014 study of people with the psychiatric disorder provided real evidence of this: The researchers found 108 distinct locations on the human genome linked to schizophrenia.
“That was a very important study,” said UCLA postdoctoral fellow Hyejung Won, first author of the new study.
Even though the 2014 research revealed parts of the genome causing schizophrenia, the results were still puzzling, Won said. These genetic loci (locations) were not in coding regions of the genome, where a genetic message is translated into proteins, which actively perform the work necessary to maintain cellular life — and our own human lives.
Instead, the loci were in regulatory regions, where genes act more or less like managers by increasing or decreasing a target gene’s activities. Another problem: No nearby targets could be found.
Searching for an explanation, Geschwind and his colleagues theorized that possible target genes may appear only far away. When the ropes of DNA underwent complex twisting and looping in order to fit into a chromosome, the regulatory genes and their as-yet-unknown targets might actually be close together.
Genetic connection points
To investigate, Geschwind and his team used a technology called chromosome conformation capture, which chemically marks and then maps the locations where loops of chromosomal DNA come into contact. And because schizophrenia is believed to result from abnormal development of the cerebral cortex, they looked at brain cells from this region.
What did Geschwind and his colleagues discover when they created a map of contact points within the chromosome?
Most of the schizophrenia-linked DNA, discovered in the 2014 study, came into contact with genes known to be crucial to brain development. This confirmed past studies indicating that genes that increase the risk for schizophrenia are “most active during early fetal brain development,” prior to 24 weeks gestation, explained Geschwind.
At this crucial moment in brain development, neurons are born and migrate to different areas of the brain.
All told, Geschwind and his team found that the schizophrenia-associated loci make up a small proportion — less than 10% — of the total genome.
“Each locus actually has very small impact in really causing schizophrenia. So it doesn’t really mean if you have one locus associated with schizophrenia, you have schizophrenia,” Won said. Rather, each locus increases the possibility of developing the disorder.
“We know that it is not caused by one gene. We call it heterogeneity: It is a disorder that can be caused by many regions, not only one region,” he said.
The new study results may someday contribute to new treatments.
“Schizophrenia is actually an adult-onset disorder, so people really didn’t think that it may have any fetal components,” Won said. “Maybe fetal brain developmental period is a very critical for the onset of this disorder, even though the onset — really showing off the symptoms — comes at a much later time.”
