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Genetic study provides first-ever insight into biological origin of schizophrenia

A landmark study, based on genetic analysis of nearly 65,000 people, has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in a gene related to “synaptic pruning” — the elimination of connections between neurons. The findings represent the first time that the origin of this devastating psychiatric disease has been causally linked to specific gene variants and a biological process. They also help explain decades-old observations: synaptic pruning is particularly active during adolescence, which is 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, which appears online in the Jan. 27, 2016 issue of Nature, was led by researchers from the Broad Institute’s Stanley Center for Psychiatric Research, Harvard Medical School, and Boston Children’s Hospital. They include senior author Steven McCarroll, director of genetics for the Stanley Center and an associate professor of genetics at Harvard Medical School; Beth Stevens, a neuroscientist and assistant professor of neurology at Boston Children’s Hospital and institute member at the Broad; Michael Carroll, a professor at Harvard Medical School and researcher at Children’s Hospital; and first author Aswin Sekar, an M.D./Ph.D. student at Harvard Medical School.

The study has the potential to reinvigorate translational research on a debilitating disease. Schizophrenia is a devastating psychiatric disorder that afflicts approximately one percent of the population and is characterized by hallucinations, emotional withdrawal, and a decline in cognitive function. These symptoms most frequently begin in patients when they are teenagers or young adults. First described more than 130 years ago, schizophrenia lacks highly effective treatments and has seen few biological or medical breakthroughs over the past half-century. In summer 2014, an international consortium, led by researchers at the Broad Institute’s Stanley Center, identified more than 100 regions in the human genome that carry risk factors for schizophrenia. The newly published study now reports the discovery of the specific gene underlying the strongest of these risk factors and links it to a specific biological process in the brain.

“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 McCarroll. “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.”

“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.”