Schizophrenia Roots Tied to Complex Web of Gene Switches

A decade-long effort by hundreds of scientists worldwide has uncovered 128 genes involved in the brain disorder schizophrenia, findings that point to new research avenues while suggesting a cure may not be achievable with a single treatment.

The roots of the illness are scattered among genes involved in learning, memory, brain signaling and even the immune system, according to a study reported today in the journal Nature.

As new technology lets scientists delve ever more deeply into the human genome, they’ve found genetic complexity in many illnesses, led by cancer. Now, the most extensive genetic analysis of schizophrenia ever ties dozens of DNA misfires to the paranoia and confusion that mark a disease afflicting about 2.4 million Americans.

It is “a molecular parts list,” that will help rev up the learning process, said Steve McCarroll, head of genetics at the Stanley Center for Psychiatric Research at the Broad Institute of the Massachusetts Institute of Technology and Harvard in Cambridge, Massachusetts. “Once you have the parts, you can start fitting them together, then you can identify ways to improve the outcomes in that system.”

While today’s medicines address the psychosis tied to the illness, they carry difficult side effects and don’t help with other symptoms, such as cognitive decline and emotional disconnection. Most importantly, the drugs aren’t a cure. The findings reported today allow a deeper view of how and why the disease forms in the first place, the researchers said.

Little Information

Previously, there was little information on why some people develop schizophrenia and others don’t, said Mark Daly, chief of analytic and translational genetics at Massachusetts General Hospital in Boston. Now, scientists may have a way to determine that, he said.

Schizophrenia generally emerges in the teens or early 20s, often robbing its victims of a normal life just as they become adults. The study analyzed the genomes of 36,989 people diagnosed with schizophrenia, compared with 113,075 healthy volunteers. Patterns are already emerging, researchers said.

Some connections among 108 regions in the genome point to pathways regulating synaptic communication, the ways neuron communicate with other neurons during the learning process, or in forming memories. Other findings include links to a small number of genes active in cells with important immune functions, particularly the white blood cells involved in acquired immunity.

Drug Treatments

Schizophrenia has been treated for more than 50 years with anti-psychotics, often supported by psychotherapy. The drugs have been thought to work by addressing a chemical imbalance in a brain region that produces dopamine, a hormone that acts as a signaler between cells. They can include side effects such as weight gain, restlessness, sleepiness and movement disorders.

While the long-suspected link to dopamine was confirmed by the new analysis, the wide range of the mutations identified should end the notion that schizophrenia is caused by a simple chemical imbalance, McCarroll said.

Each genetic finding, is “the beginnings of a clue” to be pursued, he said.

Someday, “we’ll look back at the chemical imbalance theory as medieval,” McCarroll said. “I’m hopeful these genetic results can point to a new understanding of the root cause of schizophrenia, and why all the symptoms emerge.”

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