For the first time, scientists have identified a specific gene variant that kicks a biological process called 'synaptic pruning' into overdrive, which actively increases a person's risk of developing schizophrenia - one of the most common serious mental health conditions in the world.
The causes of schizophrenia have eluded scientists for over a century, because it's virtually impossible to produce an accurate model of it in living cells or animals. But now that scientists have identified which genes are likely involved, if they can figure out how to mitigate their influence on synaptic pruning during adolescence, they'll have a good shot at developing better screening and treatment options in the future.
"For the first time, the origin of schizophrenia is no longer a complete black box," said Eric Lander, director of the Broad Institute of MIT and Harvard, who was not involved in the research.
"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."
Back in 2014, a team of researchers from Harvard Medical School performed a landmark genetic study based on 36,989 schizophrenia cases and 113,075 controls, and identified 108 regions of our DNA where genetic variants increase a person's risk of schizophrenia.
Now they've combined that with data from a genetic analysis of nearly 100,000 DNA samples from 30 countries, postmortem brain samples from almost 700 patients, and animal models looking at the biological processes involved, to identify the one gene that's associated with the highest risk of developing the disorder.
Known as complement component 4 (C4), the gene is associated with the immune system and brain development, and the researchers found that it varies in structure quite significantly between individuals. A genetic analysis of more than 65,000 people with and without schizophrenia identified that those who are carrying a particular variation of the gene - one that leads to a higher expression of it in the immune system - had a higher risk of developing schizophrenia in adolescence.
When the researchers tested this connection out in mouse models, they found that C4 is heavily involved in the process of synaptic pruning that naturally occurs in the brain as it matures through childhood and adolescence. The higher the expression of the C4 gene, the more synapses (connections between neurons) were cut away.
As Clare Wilson explains over at New Scientist, in the blood, C4 is know to bind with microbes as a signal to the immune cells that they should be 'eaten'. "By genetically engineering mice that lack C4, the team showed it has a second role - in the brain," she says. "Here, C4 binds to neurons at the points where they connect with other neurons, and signals that these connections, or synapses, should also be engulfed by immune cells."
Brain tissue analyses of human schizophrenia patients showed that they tended to have fewer connections between neurons, which provides further evidence that the presence of a highly active C4 gene variant could be cutting away neural connections in the brain, and putting an individual at an increased risk of developing the hallmarks of schizophrenia, such as hallucinations, severe emotional limitations, and a decline in cognitive function.
This is first time researchers have connected a specific genetic origin to a biological process that could be causally linked to the symptoms of this psychiatric disease. And the fact that synaptic pruning is most active in the brain during adolescence further strengthens the case for C4 being the root cause - adolescence is by far the most common age for schizophrenia symptoms to appear.
"This study marks a crucial turning point in the fight against mental illness," Bruce Cuthbert, acting director of the National Institute of Mental Health, who was not involved in the research, said in a press release. "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."
The team emphasises that treatments and potential cures are still many years down the track, and scientists still have to figure out exactly what role those specific C4 variants are playing in the process of synaptic pruning, but we've never been in a better position to address this disease, and that's something to be really excited about.
The results have been published in Nature.