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David Baxter

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Could mental illness be written in a face?
January 22, 2007
By Carey Goldberg, Boston Globe

McLean researchers explore genetic links between schizophrenia and family traits

They are not things anyone would typically notice: Do your eyes fall behind as you try to follow a cursor zipping across a computer screen? Is the roof of your mouth a touch high? Do you sometimes use words in a way that, on closer examination, does not quite make sense?

They don't matter at all in daily life, those funny little traits. But researchers at Harvard's McLean Hospital believe they may contain important clues about the elusive genes of schizophrenia, the devastating psychiatric disorder that affects 1 percent of the population.

To further explore this provocative theory, the hospital's Psychology Research Laboratory recently won a $3 million federal grant.

Consider, said Deborah Levy , the lab's director: "The incidence of schizophrenia is stable at about 1 percent, and schizophrenics have very low reproductive rates. So what is keeping those genes going? One hypothesis is that most of the people carrying the schizophrenia genes are not the patients. Rather, they are some of the well parents and well siblings, most of whom never show signs of the illness."

The idea, she and other researchers say, is that schizophrenia results from a critical combination of genes, perhaps a variable handful of them. Well relatives may carry one or more of those genes, but not the critical complement that bring on the disease.

The effects of such genes may show up in a variety of subtle ways, they say -- including faulty eye-tracking and asymmetry in facial features so hard to detect that it is best measured by highly specialized 3-D cameras.

Figuring out the genetics of a complex disease like schizophrenia is like fitting together an incredibly hard jigsaw puzzle, said Dr. Linda Brzustowicz , a psychiatrist and professor of genetics at Rutgers University who is collaborating with Levy.

Recent genomic research suggests that perhaps 15 genes may be involved in schizophrenia, she said, but "there's still a lot of murkiness," and many findings initially offer hope but then cannot be replicated.

The traits that Levy's lab is exploring are unlikely to tell the whole genetic story of schizophrenia, Brzustowicz said, and many other geneticists are pinning their hopes instead on high-powered examination of the entire genome.

But the traits are easily tested and do seem to be linked. In a jigsaw puzzle, Brzustowicz said, "the more pieces you can get in initially, the easier it is to fit in the remaining pieces. And there's no shame in starting with the corners and the edges."

Levy's approach also raises a question about whether past research overlooked genes involved in schizophrenia. Researchers have typically assumed that genes carried by healthy relatives could not contribute to risk for schizophrenia. But if the relatives actually carried the genes for traits linked to schizophrenia, it would be wrong to rule them out.

At Levy's lab, people with schizophrenia and their relatives undergo 10 to 12 hours of tests. They give blood for DNA testing. They answer questions about a wide range of symptoms. They describe what they see in inkblots. A special camera records their eye movements as they track a ball moving across a monitor. They listen to various beeps and tones as their brain responses are measured -- responses that are yet another trait Levy and others believe may be linked to schizophrenia.

The faces are measured in minute detail by Curtis Deutsch , a genetics expert who focuses on facial variations and their links to various diseases. Most people do not know it, Deutsch said, but in embryos, the brain and the face develop at around the same time from the same embryonic area and are shaped by similar forces.

So, subtle abnormalities in the shape and layout of a face may reflect specific abnormalities in brain structure, he said. Thus far, he said, he has found that some schizophrenics do have certain minor facial anomalies -- none of them visible to the naked eye -- as do some of their healthy relatives.

Deutsch and the other researchers emphasized that their testing is purely at the level of genetic research at this point. They say it would be premature to screen for signs of impending schizophrenia, though they express hope that some day, that may be possible.

For all this testing, Levy's lab pays the subjects a modest $100.

Participants, though, are not usually motivated by the money.

Peter and Doug Pease, brothers who first got tested years ago and have since recruited cousins to the cause, see the testing as a way to help schizophrenics like their beloved younger brother and families like their own.

(The brother asked Peter, a Boston lawyer, and Doug, an advertising executive, not to identify him in print, and he declined to be interviewed.)

For the two older Peases, it is as if their brother "got dealt the joker," Doug Pease said. He was full of life until the disease struck him at 18, and he ended up "shut out of any sort of normal life, of any sort of career, any sort of lasting partner relationship, lasting friendships, because he was not capable. It's criminal."

Any kind of cure seems a distant prospect, Peter said. But they wanted to contribute, Doug said, to "anything that would help unlock any answers so that other people wouldn't have to go through this."

The McLean lab is currently following about 100 such families and hoping to recruit at least 50 more, Levy said.

One of the great challenges of genetic research on schizophrenia is that though the disease clearly has a genetic component, few members of any given family actually get the disease. This makes it much harder for researchers to find the relevant genes for schizophrenia than for diseases that occur more often within families.

But the traits that Levy's lab is interested in occur at a much higher rate than schizophrenia does.

"The key value of this approach is that it amplifies the genetic signal," helping to identify healthy relatives who are carriers of the disease, said Levy, crediting her lab's approach to its founder, the late Dr. Philip Holzman.

Levy's tests detect basic brain abnormalities much as a technician can check a computer for electronic malfunctions, said Dr. Robert Freedman, editor of the American Journal of Psychiatry.

Now, using new data from the human genome, "she can begin to find the genetic changes giving rise to the abnormalities," he said. "If she can, she'll be able to connect the abnormality to the illness, and so to a change in gene, which hopefully might point the way to a specific therapy."

Carey Goldberg can be reached at goldberg@globe.com. To inquire about participating in Levy's research, contact Anne Gibbs at 617-855-3586 or agibbs@mclean.harvard.edu.
 

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