Three new genetic studies are providing some tantalizing hints about what causes schizophrenia.
The studies, published in the journal Nature, identify sections of our genetic code in which small changes can affect a person's risk for developing the disorder.
The studies found such changes in stretches of code involved in brain development, memory and the immune system.
The findings are important because schizophrenia has been so hard to study, says Kari Stefansson, CEO of the Icelandic company deCODE Genetics and an author of one of the studies. One reason is that schizophrenia doesn't occur in animals.
"It's a disease of thoughts and emotions," Stefansson says, "the two functions of the brain that define us as a species and define us as individuals."
Scientists have tried for decades to find differences between the brains of typical people and those with schizophrenia, but without much success. So Stefansson and a consortium of researchers from around the world decided to look for subtle differences in the genes of thousands of people. Some had schizophrenia; some didn't.
One place the studies found a clue about what might be going wrong in the brains of people with schizophrenia was in a gene responsible for a protein called neurogranin, which can affect memory and thought.
"The neurogranin pathway could be one of the biochemical pathways that lead to this disturbance of thought," Stefansson says.
But he says a more provocative finding is a genetic hot spot in a stretch of code that affects the immune system.
"It raises the question that somehow the tendency to develop schizophrenia may have something to do with infections of mothers during pregnancy."
The idea is that some families carry a genetic variation that affects the way the immune system responds to infection, Stefansson says. If a mother gets the flu while she's pregnant, this immune response may affect her child's brain.
It's also possible that the immune system is involved in schizophrenia in some other way, says Dr. Tom Insel, director of the National Institute of Mental Health, which helped fund the new studies.
He says the stretch of genetic code affecting immunity is pretty mysterious.
"In some ways it's a little bit like the Bermuda Triangle of the human genome," he says. "It's an area with tremendous amounts of variability. And it's an area where we often find variation that's associated with many different disorders: diabetes, rheumatoid arthritis, Crohn's disease."
In those diseases, the immune system attacks the body's own cells, a process that could also affect the brain. Researchers have suspected the immune system before, Insel says. Now, they'll probably take a harder look.
Insel says he's particularly intrigued by the finding that some genetic variations linked to schizophrenia are also linked to depression and bipolar disorder.
"It suggests, potentially, that when we're talking about the genetic factors that contribute, what we're really thinking about are genetic factors that contribute to how a brain gets built," he says.
That would mean problems in the brain start very early in life, even though the symptoms of schizophrenia may not appear for decades.
One thing the genetic studies clearly show is just how many different systems in the brain may contribute to schizophrenia, says Harvard's Dr. Pamela Sklar, an author of one of the studies.
"That's a hopeful finding because the implication is that there may be more places to intervene," she says, "if we understand the biology."