Schizophrenia has long been among the most mysterious of mental illnesses; its causes and biological risks are largely hidden away in the brain. Efforts to shed light on the condition often fall flat, leaving clinicians with very little in their arsenal to diagnose schizophrenia other than behavioral observation and interviews, let alone predict its onset before symptoms are apparent.

A landmark study led by researchers from the Broad Institute’s Stanley Center for Psychiatric Research, Harvard Medical School, and Boston Children’s Hospital has just broken an important barrier to understanding schizophrenia. For the first time, the disease has been causally linked to specific gene variants and a biological process. After delving through the genetic analyses of nearly 65,000 people, the researchers identified specific variants in a gene that significantly increased a person’s risk of schizophrenia.

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said Steven McCarroll, director of genetics for the Stanley Center and an associate professor of genetics at Harvard Medical School and senior author of the study, in a press release. “The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside, and starting to see actual biological mechanisms.”

C4: Structural Variability And Gene Activity

A team of geneticists over five years collected more than 100,000 human DNA samples from 30 different countries in an attempt to locate the regions of the human genome that harbor genetic variants that increase the risk of schizophrenia. Analysis pointed them to chromosome 6, which is found in a region of DNA that had long been associated with infectious diseases. This was a good start, but the team had no idea which of the hundreds of genes was responsible, or how they behaved.

Further analysis led the study authors to zero in on an unusual gene component complement called component 4 (C4). C4 differed from most genes in that it has a high degree of structural variability, meaning different people can have different types of the gene and a different number of copies. McCarrol and first author Aswin Sekar, of Harvard Medical School, developed a new technique to characterize the different C4 structures in human DNA samples, and measured the gene’s activity in almost 700 post-mortem brain samples.

Their work paid off; they discovered the C4 gene structure (DNA) has the ability to predict C4 gene activity (RNA) in each person’s brain. They then used this information to determine the C4 gene activity in genome data for 65,000 people with and without schizophrenia, revealing a striking correlation: Patients with a certain structural form of C4 showed higher expression of the gene, and had a higher risk of developing schizophrenia.

Cause And Effect: Pruning Synapses

Though the correlation between C4 and schizophrenia was a breakthrough, the researchers still had questions. Most pressingly, how exactly does C4, a protein known for tagging infectious microbes for destruction by immune cells, affect the risk of schizophrenia?

The team turned to its previous work with complement proteins and the immune system for insight, and made the connection that C4 played an important role in pruning synapses as the brain matured. Specifically, the team discovered C4 was responsible during the signaling part of the process, and that when there was more C4 activity in the brain, there were more neural synapses eliminated at a key time of brain development.

This finding offered possible answers for questions that had been longstanding. It may explain why the brains of people with schizophrenia tend to have thinner cerebral cortexes and fewer synapses than the brains of unaffected individuals. It also may help explain why schizophrenia symptoms tend to have an onset in late adolescence — the human brain undergoes normal, widespread synapse pruning during adolescence. The excessive synaptic pruning caused by certain types of C4 could explain the cognitive symptoms seen in schizophrenia.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” said Beth Stevens, a neuroscientist and assistant professor of neurology at Boston Children’s Hospital and member of the Broad Institute. “This discovery enriches our understanding of the complement system in brain development and disease, and we could not have made that leap without the genetics. We’re far from having a treatment based on this, but it’s exciting to think that one day, we might be able to turn down the pruning process in some individuals and decrease their risk.”

Looking Forward

Apart from providing the first insights into the biological processes behind schizophrenia, the findings provide hope for future therapies targeted at individuals showing early symptoms of schizophrenia. This would be quite unprecedented, since current medical therapies address only a specific symptom of schizophrenia (psychosis) rather than the condition’s root causes.

“This study marks a crucial turning point in the fight against mental illness,” said Bruce Cuthbert, acting director of the National Institute of Mental Health. “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments, and even prevention.”

New kinds of treatments have always been the goal, according to McCarroll.

“In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments,” he said. “These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops — something that has been greatly needed.”

Source: Sekar A, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016.