Schizophrenia Linked to 108 Genes

It took 80,000 genetic samples, seven years and the work of 300 scientists from around the world, but scientists now have the most complete dossier on schizophrenia ever.

In an historic paper published in the journal Nature, the Schizophrenia Working Group of the Psychiatric Genomics Consortium identified 108 new regions on the genome linked to the psychiatric disorder, which is associated with hallucinations and psychotic episodes and affects about 1% of people worldwide.

The genetic clues are the most dramatic hints that experts have gotten so far about what causes that mental illness. Schizophrenia has had a rocky history in the psychiatric community, with some doctors early on not even recognizing it as a disorder, and others debating whether its origins were biological or caused by traumatic events or other experiences. Now, by comparing the genomes of people with and without the disorder, it’s clear that at least some of the psychotic symptoms can be traced to changes in the genes.

“For the first time, we are starting to see the underlying biological basis of the disease, and that can lay the foundation for understanding the disorder, and eventually developing treatments,” said Eric Lander, founding director of the Broad Institute of MIT and Harvard, where about one third of the DNA samples were sequenced.

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The study used genome wide association, a technique that sequences the genomes of affected and unaffected individuals, and then compares where they differ. Those DNA differences may be hints about why people develop schizophrenia in the first place, and therefore lead to new drugs or treatments.

The 108 genetic regions aren’t all located in specific genes, nor is it known yet if this is what actually causes schizophrenia. But, like evidence at a crime scene, they may point to certain molecular pathways that are responsible for the mental illness. It’s already known that some of the identified regions, for example, are involved in how adaptable or plastic the brain is, and in regulating the immune system, a connection that experts have previously not investigated before. Other genes may also reveal new ways to potentially treat the disease, a significant improvement over the existing therapies, which only address one brain system, involving dopamine. “Thorazine was approved in 1954 as the first anti-psychotic medication, and every antipsychotic since then has relied on the same fundamental mechanism of action,” Steve Hyman, director of the Broad Institute’s Stanley Center for Psychiatric Research and professor of stem cell and regenerative biology at Harvard University said. “And their efficacy has plateaued since the 1960s.”

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Having a greater suite of potential areas of inquiry, the researchers hope, will attract pharmaceutical companies back to the field of mental illness. “We now have more than 100 genes pointing to distinct pathways – calcium channels, glutamate, the immune system – this is concrete stuff, and it means that the pharmaceutical companies who left [this area of drug development] because they didn’t have anything concrete to work on, are beginning to get their toes in the water, and are thinking of jumping back in the water,” says Lander.

The genetic windfall can also help scientists piece together how genetic changes may work in tandem to cause symptoms of psychoses. They warn that these advances, and new treatments, may not come in the next year, but they may be able to provide better answers to questions about which drugs may work better in which patients, and in finding ways to detect and hold off symptoms of schizophrenia earlier, before they become debilitating. All of the genetic information released in the paper will be deposited in a public database for researchers to access and advance the understanding of the disorder.