NEW YORK — Scientists reported Wednesday that they had taken a significant step toward understanding the cause of schizophrenia, in a landmark study that provides the first rigorously tested insight into the biology behind any common psychiatric disorder.
More than 2 million Americans have a diagnosis of schizophrenia, which is characterized by delusional thinking and hallucinations. The drugs available to treat it blunt some of its symptoms but do not touch the underlying cause.
The finding, published in the journal Nature, will not lead to new treatments soon, experts said, nor to widely available testing for individual risk. But the results provide researchers with their first biological handle on the disorder.
The finding also helps explain some other mysteries, including why the disorder often begins in adolescence or young adulthood.
The study was done by scientists from Harvard Medical School, Boston Children’s Hospital, and the Broad Institute, a research center allied with Harvard and the Massachusetts Institute of Technology.
“They did a phenomenal job,’’ said David B. Goldstein, a professor of genetics at Columbia University who has been critical of previous large-scale projects focused on the genetics of psychiatric disorders. “This paper gives us a foothold, something we can work on, and that’s what we’ve been looking for now, for a long, long time.’’
The researchers pieced together the steps by which genes can increase a person’s risk of developing schizophrenia. That risk, they found, is tied to a natural process called synaptic pruning, in which the brain sheds weak or redundant connections between neurons as it matures.
During adolescence and early adulthood, this takes place primarily in the section of the brain where thinking and planning skills are centered, known as the prefrontal cortex. People who carry genes that accelerate or intensify that pruning are at higher risk of developing schizophrenia than those who do not, the new study suggests.
Some researchers had suspected that the pruning must somehow go awry in people with schizophrenia, because previous studies showed that their prefrontal areas tended to have a diminished number neural connections, compared with those of unaffected people.
The new paper not only strongly supports that this is the case, but also describes how the pruning probably goes wrong and why, and identifies the genes responsible: People with schizophrenia have a gene variant that apparently facilitates aggressive “tagging’’ of connections for pruning, in effect accelerating the process.
The research team began by focusing on a location on the human genome, the MHC, which was most strongly associated with schizophrenia in previous genetic studies.
The team, led by Steven McCarroll, an associate professor of genetics at Harvard, and by Aswin Sekar, one of his graduate students, found that the MHC locus contained four common variants of a gene called C4, and that those variants produced two kinds of proteins, C4-A and C4-B.
The team analyzed the genomes of more than 64,000 people and found that people with schizophrenia were more likely to have overactive forms of C4-A than control subjects.
The researchers turned to Beth Stevens, an assistant professor of neurology at Boston Children’s Hospital and Harvard, who in 2007 was an author of a study showing that the products of MHC genes were involved in synaptic pruning in normal developing brains.
Mice bred without the genes that produce C4 showed clear signs that their synaptic pruning had gone awry, Stevens’s lab showed. Taken together, Stevens said, “the evidence strongly suggested that too much C4-A leads to inappropriate pruning during this critical phase of development.’’
