Schizophrenia risk gets more complex

Large collections of common genetic variants, rather than the harmful actions of just a few key mutations, probably predispose people to schizophrenia, three large genetic studies suggest.

The studies, all published online July 1 in Nature, sifted through mountains of genetic data from patients with schizophrenia and people without the disease looking for spelling differences in the sequence of letters that make up the genome. The studies also turned up specific chromosome regions that probably play a role in the disease. Understanding such genetic factors, estimated to account for 80 percent of the total risk of getting schizophrenia, may ultimately lead to better treatments.

“This is a pretty major breakthrough for us,” said Michael O’Donovan of Cardiff University’s School of Medicine in Wales at a July 1 press briefing. O’Donovan coauthored one of the studies as part of the International Schizophrenia Consortium. He says a person with schizophrenia probably has hundreds or thousands of risk-increasing variants.

Using a method called genome-wide association, each of the three studies compared several thousand DNA samples from people diagnosed with schizophrenia with samples from thousands of others, some healthy and some with other diseases. Association studies are designed to find single letter differences, called SNPs, at many points along the DNA. Such variants popping up more frequently in the schizophrenia patients’ DNA are presumed to markers of regions of the genome that contribute to the disease.

Many thousands of common DNA variants (those found in about 5 percent of the total population) turned up more often in people with schizophrenia, the new studies found. “This is the first empirical DNA-based evidence” for many small genetic effects adding up to schizophrenia, says Pamela Sklar of Massachusetts General Hospital and Harvard University, who coauthored the consortium study.

On their own, each variant identified in the new studies raises the risk of schizophrenia just slightly — from 1 percent (the risk in the general population) to, in some cases, around 1.2 percent. Collectively, common variants may account for about a third of the overall genetic risk of schizophrenia, Sklar says. Other factors that contribute to genetic risk include variations in the number of copies of certain genes and rare but high-risk variants of specific DNA letters.

Researchers will need much larger samples of schizophrenia patients’ DNA to identify all the genetic variants that heighten disease risk. “We fully expect that as the sample sizes get bigger, we’ll refine the genes involved,” Sklar says.

Although few of the variants could be identified conclusively by these studies, some of the variants were found in stretches of the genome previously linked to schizophrenia. Such regions occurred near genes involved in the formation of brain cell connections and genes involved in controlling the activity of other genes.

“The interesting thing about taking these together is that we start to identify pathways involved in the disease,” David Collier of King’s College London, a coauthor of the second paper, said in the press briefing. “This, I think, could really point the way to mechanisms of the disease and potential therapeutic interventions at different sites within these pathways.”

DNA variations in a region of chromosome 6 called the major histocompatibility complex were also found in the schizophrenia patients’ DNA in all three studies. This region contains genes that make proteins that are important for immune system function. Earlier studies have suggested a link between disruptions in the immune system with a heightened risk of schizophrenia.

“It’s extremely provocative to have an association there. We have not found an explanation. It is there and we do not know why,” says Pablo Gejman, a psychiatric geneticist at NorthShore University HealthSystem Research Institute in Evanston, Ill., and coauthor of the third study. “This is the start. This is not the last chapter.”

If the link between immunity and schizophrenia is confirmed, treatments for autoimmune diseases may also prove useful for alleviating the psychiatric disease, says clinical pharmacist Donald Rogers of the State Office of Pharmacy in Tewksbury, Mass. Rogers estimates that currently only 30 to 40 percent of schizophrenia patients respond well to treatments. “It’s unacceptable that 60 percent live with this debilitating disease,” he says.