Scientists pin down molecular process linked to schizophrenia origin

By Sally Robertson, B.Sc.Jan 28 2016

For the first time, researchers have managed to home in on a molecular process in the brain that contributes to the development of schizophrenia.

The landmark study, which was based on a genetic analysis of almost 65,000 people, showed that a person’s risk of developing schizophrenia is significantly increased if they inherit variants of a gene called complement component 4 (C4). This gene is key to a process called “synaptic pruning,” which refers to the healthy elimination of brain cell connections that are no longer needed, during adolescence.

In patients with schizophrenia, a variant in a single position in the DNA sequence of C4, flags synapses up for removal. Synaptic pruning then spirals out of control, resulting in an abnormal loss of grey matter. Essentially, neurons become coated in “eat-me signals” and too many of them are “gobbled up,” explains one of the study’s authors, Beth Stevens (Broad Institute's Stanley Center for Psychiatric Research).

This is the first time that the origin of schizophrenia has been causally linked to a gene variant and biological process and the researchers say their study offers a new way of approaching schizophrenia research. "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," explains lead author Steven McCarroll (Harvard Medical School)…

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.

In July 2014, researchers from the Broad Institute's Stanley Center for Psychiatric Research published results from the largest genomic study of schizophrenia to date, which identified over 100 genetic locations associated with development of the disease. Based on those findings, McCarroll and team assessed data from 29,000 schizophrenia patients, 36,000 control individuals and 700 post-mortem brains. They found that individuals with certain structural forms of the C4 gene expressed more of that gene and, in turn, were at a greater risk of developing schizophrenia.

Director of the Broad Institute, Eric Lander, says: "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.”