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April 8, 2013

Schizophrenia Gene Puzzle

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Scientists are trying to decode the genetic causes of schizophrenia. But as this ScienCentral News video explains, new research suggests that nearly every person with the illness has a different genetic defect.

[If you cannot see the youtube video below, you can click here for a high quality mp4 video.]

Interviewees: Cynthia, has schizoaffective disorder;
Jon McClellan, Seattle Children's Hospital
Length: 1 min 39 sec
Produced by Sandy Chase
Edited by Sandy Chase and Chris Bergendorff
Copyright © ScienCentral, Inc.

Hearing Voices

She's working productively now, but Cynthia, who prefers not to reveal her last name, struggled for much of her adult life with schizophrenia, a mental illness that can cause confusion, paranoia, and hallucinations. She says one of the scariest symptoms was hearing voices. "Because sometimes the voices could have you to act out, you know in a certain behavior, you know, be explosive, yelling at somebody." Technically, her illness is called schizoaffective disorder because it also includes symptoms of bipolar disorder.

Schizophrenia can run in families, as it does in Cynthia's family, but most cases seem to come out of the blue. Psychiatrist Jon McClellan of Seattle Children's Hospital says that's one reason finding a genetic cause of the illness is difficult.

"Typically the way it works now-and it's common sense-you start with everybody that has the same syndrome, whether it's schizophrenia or autism or bipolar disorder, and then you try to see what genetic markers they share, with the assumption that because they have the same illness, they must share some similar genetic cause"

But schizophrenia does not fit that model. So far, a single genetic cause has been elusive.

Expanding the Search

McClellan and colleagues at the University of Washington, Seattle published a paper in the journal Science explaining a different approach. They examined the entire genome of 150 people with schizophrenia and 268 controls, looking for repeats or deletions-called copy number variants-in small stretches of subjects' DNA.

Scientists now say schizophrenia might be caused by mutations or copy number variants in brain development genes, which are distributed throughout the genome.

All humans have some copy number variants in their DNA, and the researchers assumed that the common ones were not harmful. But 15 percent of the schizophrenia group had rare variants-caused by small mutations-compared to five percent of controls. Another team at the National Institute of Mental Health examined 83 people with early-onset schizophrenia (a more severe form of the illness) and found that 20 percent of those people had rare variants in their DNA.

When the teams examined what those genes do, they found that most often, they were related to brain development.

So then what genes cause schizophrenia? This is where the answer becomes more complicated. McClellan explains, "What was interesting about it is that every patient where we found one of these mutations, the mutation was different, that each one involved a different gene."

It may turn out that nearly every case of schizophrenia is caused by a unique genetic change. But that doesn't rule out finding better treatments. McClellan says new therapies may come out of what those genes have in common. "So, even though it may be that most cases have a different gene that's involved, if several of those genes work within the same brain system, then treatments can be developed to stabilize that brain system no matter what was the cause of why it was disrupted."

The researchers are going back now and reexamining the DNA of the test subjects with a finer-toothed comb. Originally, they looked at repeats or deletions that were 100,000 base pairs or longer. Their new analysis has a resolution of 3,000 base pairs. They hope to find incidents of genetic disruptions that the first analysis may have missed.

This same approach may shed light onto other mysterious neurological conditions that have a strong genetic component.

"There's already been similar findings for both autism and mental retardation," says McClellan, "and they'll probably continue to be interesting findings for all neuropsychiatric disorders as these technologies improve."

Hope and Respect

In Cynthia's case, current medications have stabilized her illness. She sees a therapist regularly, and has been out of hospitals for 11 years now. She volunteers at her local New York City National Alliance on Mental Illness office, doing office work and teaching crocheting. She says one of the biggest challenges is overcoming the stigma of mental illness. "I would say to people, you know, try to understand what mental illness is all about, and don't make fun if you see someone that has mental illness, because unfortunately it can happen to anybody."

She spoke recently at a NAMI fundraising walk in New York City, reminding the crowd that no matter what causes schizophrenia, it's the person, not the illness, that counts. "We may have a mental illness, but it does not define who we are. We are still fun, loving, caring people with a life!"

PUBLICATION: Science, April 2008.

RESEARCH FUNDED BY: The Forrest C. and Frances H. Lattner Foundation; NARSAD; The Simons Foundation; The Stanley Medical Research Foundation; the Howard Hughes Medical Institute; National Institutes of Health; National Institute of Mental Health; Washington State Department of Social and Health Services.


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