By Amy Ellis Nutt
January 27, 2016
For the first time, scientists have pinned down a molecular process in the brain that helps to trigger schizophrenia. The researchers involved in the landmark study, which was published Wednesday in the journal Nature, say the discovery of this new genetic pathway probably reveals what goes wrong neurologically in a young person diagnosed with the devastating disorder.
The study marks a watershed moment, with the potential for early detection and new treatments that were unthinkable just a year ago, according to Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute at MIT. Hyman, a former director of the National Institute of Mental Health, calls it "the most significant mechanistic study about schizophrenia ever."
"I’m a crusty, old, curmudgeonly skeptic," he said. "But I’m almost giddy about these findings."
The researchers, chiefly from the Broad Institute, Harvard Medical School and Boston Children's Hospital, found that a person's risk of schizophrenia is dramatically increased if they inherit variants of a gene important to "synaptic pruning" -- the healthy reduction during adolescence of brain cell connections that are no longer needed.
In patients with schizophrenia, a variation in a single position in the DNA sequence marks too many synapses for removal and that pruning goes out of control. The result is an abnormal loss of gray matter.
The genes involved coat the neurons with "eat-me signals," said study co-author Beth Stevens, a neuroscientist at Children's Hospital and Broad. "They are tagging too many synapses. And they're gobbled up."
The Institute's founding director, Eric Lander, believes the research represents an astonishing breakthrough. "It’s taking what has been a black box...and letting us peek inside for the first time. And that is amazingly consequential," he said.
The timeline for this discovery has been relatively fast. In July 2014, Broad researchers published the results of the largest genomic study on the disorder and found more than 100 genetic locations linked to schizophrenia. Based on that research, Harvard and Broad geneticist Steven McCarroll analyzed data from about 29,000 schizophrenia cases, 36,000 controls and 700 post mortem brains. The information was drawn from dozens of studies performed in 22 countries, all of which contribute to the worldwide database called the Psychiatric Genomics Consortium.
One area in particular, when graphed, showed the strongest association. It was dubbed the “Manhattan plot” for its resemblance to New York City's towering buildings. The highest peak was on chromosome 6, where McCarroll’s team discovered the gene variant. C4 was "a dark corner of the human genome," he said, an area difficult to decipher because of its "astonishing level" of diversity.
C4 and numerous other genes reside in a region of chromosome 6 involved in the immune system, which clears out pathogens and similar cellular debris from the brain. The study's researchers found that one of C4's variants, C4A, was most associated with a risk for schizophrenia.
More than 25 million people around the globe are affected by schizophrenia, according to the World Health Organization, including 2 million to 3 million Americans. Highly hereditable, it is one of the most severe mental illnesses, with an annual economic burden in this country of tens of billions of dollars.
"This paper is really exciting," said Jacqueline Feldman, associate medical director of the National Alliance on Mental Illness. "We as scientists and physicians have to temper our enthusiasm because we’ve gone down this path before. But this is profoundly interesting."
There have been hundreds of theories about schizophrenia over the years, but one of the enduring mysteries has been how three prominent findings related to each other: the apparent involvement of immune molecules, the disorder's typical onset in late adolescence and early adulthood, and the thinning of gray matter seen in autopsies of patients.
"The thing about this result," said McCarroll, the lead author, " it makes a lot of other things understandable. To have a result to connect to these observations and to have a molecule and strong level of genetic evidence from tens of thousands of research participants, I think that combination sets [this study] apart."
The authors stressed that their findings, which combine basic science with large-scale analysis of genetic studies, depended on an unusual level of cooperation among experts in genetics, molecular biology, developmental neurobiology and immunology.
"This could not have been done five years ago," said Hyman. "This required the ability to reference a very large dataset . ...When I was [NIMH] director, people really resisted collaborating. They were still in the Pharaoh era. They wanted to be buried with their data."
The study offers a new approach to schizophrenia research, which has been largely stagnant for decades. Most psychiatric drugs seek to interrupt psychotic thinking, but experts agree that psychosis is just a single symptom -- and a late-occurring one at that. One of the chief difficulties for psychiatric researchers, setting them apart from most other medical investigators, is that they can't cut schizophrenia out of the brain and look at it under a microscope. Nor are there any good animal models.
All that now has changed, according to Stevens. "We now have a strong molecular handle, a pathway and a gene, to develop better models," he said.
Which isn't to say a cure is right around the corner.
"This is the first exciting clue, maybe even the most important we’ll ever have, but it will be decades" before a true cure is found," Hyman said. "Hope is a wonderful thing. False promise is not."