A new genetic analysis of people with schizophrenia — and the largest study investigating the genetic basis of any psychiatric disorder to date — provides hints that the disease may sometimes be connected with infections as some researchers have long suggested.

These findings could one day lead to new therapies for people with schizophrenia, scientists said. There have been few innovative drug treatments for schizophrenia over the last 60 years.

"In the past, people thought schizophrenia must happen because of some really bad mutations in a person not seen in people around them," said study co-author Steve McCarroll, director of genetics at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. "This study shows a substantial part of the risk of schizophrenia comes from many tiny nudges to the genome that all humans share."

Schizophrenia affects about one out of every 100 people worldwide, and tends to emerge during the teens and early 20s. People with the disorder may have hallucinations, delusions, reduced emotional responses and a breakdown of thought processes.

The medications currently on the market for schizophrenia treat only one class of its symptoms — hallucinations and delusions — and do not address the debilitating effects the disorder can have on patients' emotional responses or thought processes. And no medications with fundamentally new ways of treating schizophrenia have been developed since the 1950s.

Part of the reason the treatment options are so limited is that the biological mechanisms underlying schizophrenia remain poorly understood. All existing approved drugs for schizophrenia attack the same molecules in the brain — proteins linked with the brain chemical dopamine — and researchers only discovered this strategy for treatment by accident. However, previous studies have hinted that schizophrenia is caused by the combined effects of many different genes. [5 Controversial Mental Health Treatments]

The genetics of schizophrenia

To see which locations in the human genome may be linked to any given specific trait, such as a disease, researchers often carry out what are called genome-wide association studies. These involve scanning people's entire genomes to look for mutations that are more common in people with a disease than in those without it. The locations in the genome where the differences reside can provide valuable clues about the causes of the disease.

Prior studies had identified only about 30 locations in the human genome associated with the risk of developing schizophrenia. Now, the new research brings the total to more than 100.

"Thirty years ago, genetics played an important role in opening up the problem of cancer, and I think genetics could play a similar role in schizophrenia now," McCarroll said. Cancer patients now have far better treatment options than they did 30 years ago, he said. "We may be at the beginning of similar discoveries with schizophrenia."

In this new genome-wide association study, researchers investigated nearly 37,000 schizophrenia patients and more than 113,000 people without schizophrenia. The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium, an international collaboration that conducts broad-scale analyses of genetic data for psychiatric disease.

The scientists found 108 locations in the human genome associated with risk for schizophrenia, including 83 loci, as scientists refer to the sites in the genome, which had not previously been linked to the disorder.

What these genes do

"Many of the genetic variations we found are common — every human being has dozens of genetic variations that appear to contribute to risk of schizophrenia," McCarroll said. "Schizophrenia patients, on average, have more of these variants than unaffected individuals, but that's only true on average."

The researchers can now group these genetic changes based on the pathways they are involved in, or the functions they perform, said lead study author Stephan Ripke, also of the Broad Institute. "This is helping us to understand the biology of schizophrenia."

For example, many of these loci are genes involved in how signals get transmitted between cells in the brain, and a number are active within immune cells. This may support the so-called germ theory of schizophrenia, which suggests that some fraction of schizophrenia cases may be due to problems with infections. Another possibility is that immune cells might malfunction in some schizophrenia patients and attack their brains, causing the disorder.

However, McCarroll cautioned that although these genes are active in immune cells, the genes might play a completely different role in the brain. "We have to be humble and careful with our interpretation of these results," he said.

The researchers also found a link between schizophrenia and the gene that produces the dopamine-linked molecule that is targeted by all existing approved medications for schizophrenia. This suggests that other loci uncovered by this new study may point to more potential targets for therapies.

The scientists detailed their findings online July 21 in the journal Nature.

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