Genome sequencing method helps reveal origin of schizophrenia

In a breakthrough study, a team of researchers at the Broad Institute's Stanley Center for Psychiatric Research (Cambridge, MA), Harvard Medical School (Cambridge), and Boston Children's Hospital (Boston, MA) performed genetic analysis of nearly 65,000 human genomes using a genome sequencing method, revealing that a person's risk of schizophrenia is increased if they inherit specific variants in a gene related to eliminated connections between neurons (known as synaptic pruning).

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The findings show that the origin of schizophrenia has been causally linked to specific gene variants and a biological process, and helps explain that synaptic pruning is particularly active during adolescence (the typical period of onset for schizophrenia symptoms) and brains of schizophrenic patients tend to show fewer connections between neurons. The gene, called complement component 4 (C4), plays a well-known role in the immune system, but has now been shown to also play a key role in brain development and schizophrenia risk. The insight may allow future therapeutic strategies to be directed at the disorder's roots rather than just its symptoms.

The study involved the collection of DNA from more than 100,000 people, detailed analysis of complex genetic variation in more than 65,000 human genomes, development of an innovative analytical strategy, examination of postmortem brain samples from hundreds of people, and the use of animal models to show that a protein from the immune system also plays a previously unsuspected role in the brain.

Over the past five years, geneticists led by the Broad Institute's Stanley Center for Psychiatric Research and its collaborators around the world collected more than 100,000 human DNA samples from 30 different countries to locate regions of the human genome harboring genetic variants that increase the risk of schizophrenia. The strongest signal by far was on chromosome 6, in a region of DNA long associated with infectious disease, causing some observers to suggest that schizophrenia might be triggered by an infectious agent. But researchers had no idea which of the hundreds of genes in the region was actually responsible or how it acted.

Based on analyses of the genetic data, senior author Steven McCarroll, director of genetics for the Stanley Center and an associate professor of genetics at Harvard Medical School, and Aswin Sekar, an MD/PhD student at Harvard Medical School, focused on a region of the brain containing the C4 gene. Unlike most genes, C4 has a high degree of structural variability, as different people have different numbers of copies and different types of the gene. McCarroll and Sekar used a genome sequencing technique called digital droplet polymerase chain reaction (ddPCR) to characterize the C4 gene structure in human DNA samples. They also measured C4 gene activity in nearly 700 postmortem brain samples. They found that the C4 gene structure (DNA) could predict the C4 gene activity (RNA) in each person's brain, and used this information to infer C4 gene activity from genome data for 65,000 people with and without schizophrenia. Patients who had particular structural forms of the C4 gene showed higher expression of that gene and, in turn, had a higher risk of developing schizophrenia.

Seeking to answer how C4 affects the risk of schizophrenia, Beth Stevens, a neuroscientist and assistant professor of neurology at Boston Children's Hospital and Broad Institute institute member, found that other complement proteins in the immune system also played a role in brain development by studying an experimental model of synaptic pruning in the mouse visual system. Michael Carroll, a professor at Harvard Medical School and researcher at Boston Children's Hospital, had long studied C4 for its role in immune disease, and developed mice with different numbers of copies of C4. They found that C4 played a key role in pruning synapses during maturation of the brain and, in particular, that C4 was necessary for another protein (a complement component called C3) to be deposited onto synapses, as a signal that the synapses should be pruned. The data also suggested that the more C4 activity an animal had, the more synapses were eliminated in its brain at a key time in development.

The findings may help explain the longstanding mystery of why brains from people with schizophrenia tend to have a thinner cerebral cortex with fewer synapses than unaffected individuals do. The work may also help to explain why the onset of schizophrenia symptoms tends to occur in late adolescence, as the human brain normally undergoes widespread synapse pruning during adolescence, especially in the cerebral cortex (which is responsible for many aspects of cognition). Excessive synaptic pruning during adolescence and early adulthood because of increased C4 activity could lead to the cognitive symptoms seen in schizophrenia.

Beyond providing insights into the biological origins of schizophrenia, the work raises the possibility that therapies might someday be developed that could "turn down" the level of synaptic pruning in individuals who show early symptoms of the disorder. This would be a dramatically different approach from current medical therapies, which address only a specific symptom of schizophrenia (psychosis) rather than the disorder's root causes, and do not stop cognitive decline or other symptoms of the illness.

The researchers emphasize that therapies based on these findings are still years down the road, but the fact that much is already known about the role of complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anti-complement drugs are already under development for treating other diseases.

Full details of the work appear in the journal Nature; for more information, please visit http://dx.doi.org/10.1038/nature16549.

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