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 likely 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 the Massachusetts Institute of Technology. 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 Children's Hospital in Boston, 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 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 founding director of the Broad Institute, Eric Lander, thinks 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 geneticist Steven McCarroll analyzed data from some 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 Genome 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.
There have been hundreds of theories about this mental illness 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 in the disorder, the age of its 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, "it makes a lot of other things understandable."
More than 2 million people in the United States have been diagnosed with schizophrenia.