Schizophrenia breakthrough as genetic study reveals link to brain changes

Discovery of a link between genes which play a key role in brain development and a heightened risk of schizophrenia raises hopes for future therapies
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Steven McCarroll, the director of the Stanley Centre for Psychiatric Research, Beth Stevens, an assistant professor of neurology at Boston Children’s Hospital, and Eric Lander, the director of the Broad Institute, discuss efforts to understand if there is a link between molecular and cellular events and the development of schizophrenia. Source: The Broad Institute

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People are more at risk of schizophrenia if they inherit genes that lead to excessive loss of healthy brain synapses during adolescence, a major US study suggests.
Schizophrenia is known to have a genetic component but the research, published online in Nature on Wednesday, links the disease with specific gene variants and a biological process called synaptic pruning - the elimination of connections between neurons, or brain cells.
Treatment of schizophrenia is currently limited to addressing one specific symptom of the disease, psychosis. But the breakthrough by researchers from the Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard raises hopes that therapies could eventually be developed - although they remain a long way off - which help address the root causes, by limiting the paring of healthy cells. 
Eric Lander, director of the Broad Institute, said: “For the first time, the origin of schizophrenia is no longer a complete black box. While it’s still early days, we’ve seen the power of understanding the biological mechanism of disease in other settings. Early discoveries about the biological mechanisms of cancer have led to many new treatments and hundreds of additional drug candidates in development. Understanding schizophrenia will similarly accelerate progress against this devastating disease that strikes young people.”
The researchers analysed 100,000 human DNA samples from 30 different countries to locate genetic variants in a region of the human genome that increases the risk of schizophrenia. They homed in on a gene called complement component 4 (C4), which is part of the immune system.
Unlike most genes, C4 has a high degree of structural variability between different people. Genetic analysis of more than 65,000 people found that those who had particular forms of the gene showed higher expression of that gene and, in turn, had a higher risk of developing schizophrenia.
Analysis on mice suggested that this was because in addition to its contribution to the immune system, C4 plays a key role in pruning synapses during maturation of the brain. The more C4 activity an animal had, the more connections between cells were eliminated at a key time in development.
Schizophrenia symptoms, which include hallucinations, emotional withdrawal, and a decline in cognitive function, tend to materialise in late adolescence and the work may provide a clue as to why this is so. 
The human brain normally undergoes widespread synapse pruning during adolescence, but excessive paring during this period, due to increased C4 activity, could lead to the cognitive symptoms seen in schizophrenia.
The work raises the possibility that in the future therapies could be developed that could “turn down” the level of synaptic pruning in individuals who show early symptoms of schizophrenia. 
Bruce Cuthbert, acting director of US federal agency, the National Institute of Mental Health, described the study as “a crucial turning point in the fight against mental illness”.
Other experts similarly praised it as an important piece of research, but warned that it was just one piece of a puzzle comprising other genetic variants. 
Prof Mike Owen, director of the MRC centre for neuropsychiatric genetics and genomics, Cardiff University, said: “New research will be needed to understand exactly how C4 plays a role in synaptic pruning and schizophrenia and how this process interacts with other genes and proteins that have been implicated in the disorder. Treatment implications are unclear at the present time but this new work points the finger at a particular process and implicates a set of potential new targets which will need to be explored in experimental systems.” 
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