McLean Researchers Using Novel Method to Identify Schizophrenia Genes

July 25, 2006

Cynthia Lepore
Public Affairs

Belmont, MA - Researchers at Harvard-affiliated McLean Hospital have received a $3-million federal grant to look for genes linked to schizophrenia in individuals with a diagnosis of schizophrenia and their families.

Researchers believe that several genes may play a role in schizophrenia, a chronic and disabling brain disease marked by such symptoms as emotional withdrawal, extreme paranoia, hallucinations and the belief that others are controlling one's thoughts.

"There are a number of genes or chromosomal regions that appear to be linked to schizophrenia," said Deborah Levy, PhD, director of McLean Hospital's Psychology Research Laboratory. "But we do not know which of these linkages are correct. Nobody has identified with certainty any gene that is conclusively linked to schizophrenia although there are a number of promising leads."

In families with schizophrenia, approximately 6.5 percent of relatives actually have the illness, which afflicts less than one percent of the general population. "One of the key issues in any genetic study is that you have to be able to distinguish individuals who are gene carriers from individuals who are not gene carriers," Levy said. In single gene disorders, such as cystic fibrosis and Huntington's disease, 25 percent and 50 percent of family members, respectively, have the same illness. Because only 6.5 percent of family members of individuals with schizophrenia actually have the illness, the vast majority of relatives do not have symptoms of the illness. Yet, some of them are likely to be gene carriers even though the gene is not expressed as schizophrenia.

Levy and her colleagues have developed a novel method that may help to identify relatives who are carriers of schizophrenia genes even though they do not have the illness. "One important clue," Levy said, "is that a large proportion of well family members exhibit a number of discernable traits associated with schizophrenia. These schizophrenia-related traits are much more benign than a chronic psychotic condition like schizophrenia."

The traits identified by the McLean researchers include a subtle form of thinking disturbance that involves idiosyncratic use of language; difficulty following slowly moving targets with their eyes; and a slight anomaly in facial structure detectable only through precise measurement of facial features.

Thought disorder, for example, occurs in 37 percent of clinically unaffected first-degree relatives of individuals with schizophrenia, a rate that is almost six times higher than schizophrenia in the same families and more than three times higher than in the general population. When the rates for thought disorder, schizophrenia and related clinical conditions are combined, the proportion of potential gene-carrying relatives is close to 50 percent, consistent with a dominant gene, and much higher than the 6.5 percent rate of schizophrenia in the same families.

"The idea is that a single gene can manifest itself in several different ways. One of several genes for schizophrenia can also be a major gene for one of the identified traits. Because schizophrenia-related traits are so much more prevalent than schizophrenia in families, it is easier to find the schizophrenia genes by finding genes for the schizophrenia-related traits." Levy said.

In addition to investigating whether previously implicated genes and chromosomal regions play a role in genetic vulnerability to schizophrenia, the researchers will also look for new genes, using these more prevalent associated traits as pointers. Levy noted that genes might have been missed because some psychiatrically well relatives who are gene carriers were erroneously classified as non-gene carriers.

The study, funded by the National Institute of Mental Health, will run for five years. The team of researchers from McLean will collaborate with molecular geneticists from Rutgers University, Cold Spring Harbor Laboratory in New York, University of Colorado, and University of Toronto; a behavioral geneticist at the Shriver Center in Waltham, Mass., and statistical geneticists at the State University of New York at Stony Brook.

Levy said she is very optimistic about the prospects for the study. "This kind of work has a lot of implications for early detection and early intervention. Once you identify the genetic error, you can discover the biological processes they initiate in the brain and potentially develop treatments that alter or correct it."

U.S. News & World Report consistently ranks McLean Hospital the nation's top psychiatric hospital. McLean is an affiliate of Harvard Medical School and Massachusetts General Hospital, and a member of Partners HealthCare.

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