Genetic and biomedical researchers have made yet another tremendous breakthrough from analyzing the human genome. This time a group of scientists, from Harvard Medical School, Boston Children’s Hospital and the Broad Institute, have identified key genetic markers and biological pathways that underlie schizophrenia.
In the US alone the psychiatric disorder affects around 2 million people. Symptoms of schizophrenia usually include hallucinations, delusional thinking and paranoia. While there are a number of drugs used to treat its symptoms, and psychotherapy to address milder forms, nothing as yet has been able to address its underlying cause(s). Hence the excitement.
Scientists reported on 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 two 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 an ancient disorder whose cause has confounded modern science for generations. The finding also helps explain some other mysteries, including why the disorder often begins in adolescence or young adulthood.
“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 activity 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 of 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. On a bar graph — called a Manhattan plot because it looks like a cluster of skyscrapers — the MHC looms highest.
Using advanced statistical methods, the team 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 the overactive forms of C4-A than control subjects. “C4-A seemed to be the gene driving risk for schizophrenia,” Dr. McCarroll said, “but we had to be sure.”
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