Landmark genetic study of schizophrenia uncovers its biological underpinnings

By John Murphy, MDLinx
Published January 28, 2016

Key Takeaways

Researchers have used genetics to find the underlying biological mechanisms for schizophrenia, according to a study published online January 27, 2016 in the journal Nature. Hailed as a landmark discovery, this research opens the “black box” of the psychiatric disorder’s unexplained pathogenesis, researchers said.

“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, PhD, Associate Professor in the Department of Genetics at Harvard Medical School, and Director of Genetics at Broad Institute’s Stanley Center for Psychiatric Research, in Cambridge, MA.

“The human genome is providing a powerful new way into this disease,” he added. “Understanding these genetic effects on risk is a way of prying open that block box, peering inside, and starting to see actual biological mechanisms.”

That biological mechanism, the researchers concluded, involves specific yet variable immune system genes that are linked to the “pruning” of synapses during late adolescence—the same time when schizophrenia symptoms usually appear. These findings may one day result in diagnostic tests and treatments for schizophrenia, researchers predicted.

The C4 gene stands out

This new discovery stems from a large genome-wide association study, published in July 2014, which found more than 100 specific genetic loci associated with a risk for schizophrenia. Among these, researchers found significant risk association in the major histocompatibility complex (MHC), a wide-spanning region associated with immunity.

Within the MHC, the strongest risk by far appeared at the complement component 4 (C4) gene. When researchers plotted the MHC’s genetic risk factors on a graph, the C4 gene stood out—it towered high above other risk-associated areas on schizophrenia’s genomic “skyline.”

In humans, C4 exists as two functionally distinct genes: C4A and C4B. Also, unlike most genes, C4 has a high degree of structural variability—the number of copies of the genes, as well as the types (long and short), vary from person to person. To make sense of this, the researchers developed a new molecular technique to accurately assess the number of copies and the types of each gene.

They found that different genetic combinations of copies and types of C4 were associated with different levels of risk. To better characterize this, they used RNA data to track C4A and C4B activity, which showed that C4A and C4B expression increased with the number of the gene copies as well as the ratio of the gene types.

This also revealed a striking association: The higher the levels of C4A expression, the greater the risk of schizophrenia.

The synapse gets pruned

To test this hypothesis, the researchers turned to a mouse model. In the immune system, C4 plays a key role in “synaptic refinement”—the pruning of synapses during maturation of the brain. The researchers discovered that during postnatal brain maturation in mice, C4 deposits C3 (another complement component) onto synapses as a marker to show phagocytic cells which synapses to prune. The more C4 activity an animal had, the more synapses were eliminated in its brain at this key time in development.

In humans, this pruning occurs in the late teens and early adulthood, which notably coincides with the typical onset of schizophrenia symptoms in late adolescence. Thus, increased C4 activity could drive excessive synaptic pruning during adolescence and early adulthood, and lead to the cognitive symptoms seen in schizophrenia. These findings may also explain why people with schizophrenia tend to have a thinner cerebral cortex with fewer synapses in the brain, the researchers hypothesized.

“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, PhD, a neuroscientist and Assistant Professor of Neurology at Boston Children’s Hospital, who pioneered the research of synapse pruning in the mouse brain.

“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,” she added.

“This study marks a crucial turning point in the fight against mental illness. It changes the game,” said Bruce Cuthbert, PhD, acting director of the National Institute of Mental Health, which helped fund the research. “Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments, and even prevention.”

In this video from the Broad Institute, the researchers describe the science behind the discovery.

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