Schizophrenia is a devastating and mysterious disease that strikes one person in a hundred, but scientists have taken an important step toward identifying the genes that increase individual susceptibility to this severe mental affliction.
In the largest study of the relationship between genes and schizophrenia yet undertaken in North America, a multi-disciplinary group of researchers have looked intensively at four specific chromosomes to determine whether they contain genes that contribute to this common mental malady.
Speaking on Sunday, Dec. 9, at the annual meeting of the American College of Neuropsychopharmacology held in Waikoloa, Hawaii, Debby Tsuang of the University of Washington - a member of the molecular genetics team - reported that she and her colleagues have found evidence for such an association in two of the chromosomes - 13 and 15 - and no such evidence in the other two - 12 and 16. The positive findings on chromosomes 13 and 15 confirm the results reported by several other investigators.
Previous studies have implicated genes on a number of different chromosomes with schizophrenia. For some time, twin, adoption and family studies have indicated that genes influence an individual's susceptibility of developing schizophrenia. But studies that have claimed to isolate the specific genes involved have been difficult to repeat and, in some cases, have come to conflicting conclusions.
According to Tsuang, the study, called the Veterans Administration Cooperative Study Sample, sheds new light on the confusing situation. It is the first such study to include large samples of European-American and African-American families from the United States. As a result, the researchers were able to determine that the association between chromosome 15 and schizophrenia in European-American families was positive while there was no association between the chromosome and the incidence of schizophrenia in the African-American families.
"This was one of the strongest results of our analysis," said Tsuang. "It means that different combinations of genes may contribute to schizophrenia in different ethnic groups."
A commonly held view among researchers is that susceptibility to schizophrenia results from the interaction of a large number of genes, each of which has a small individual effect. Chromosomes 13 and 15 likely harbor several of these genes. These genetic factors interact with environmental influences that also can be very significant. The finding that the genetic factors underlying schizophrenia varies among different ethnic groups may help explain why studies done with groups of differing ethnicity may have come to different or conflicting results, Tsuang observed.
The link between chromosome 15 and schizophrenia in European-Americans replicate the findings of an earlier study. More recently, this link has also been reported in schizophrenic patients of Taiwanese and Portuguese descent.
Tsuang's analysis was based on a sample of 166 families with two or more individuals who were diagnosed with schizophrenia who were recruited by seven VA Medical Centers around the country. The sample was assembled with the goal of identifying the genes that confer susceptibility for schizophrenia. Clinicians at VA Medical Centers in Brockton/West Roxbury, MA; Waco, TX; Danville, IL; Augusta, GA; Tuskegee, AL; Pretty Point, MD; New Orleans, LA and Northport, NY conducted the detailed interviews of the affected individuals and their family members. Laboratories at the University of Washington performed the DNA analyses while the statistical analyses were done at the University of Michigan.
The regions on chromosome 13 and 15 that show a positive linkage to schizophrenia contain hundreds of genes that could contribute to the condition. "Currently, there is no good way to decipher which of these genes is directly responsible," Tsuang cautioned. To identify the individual genes involved would require narrowing these regions to a more manageable size for genetic analysis and that, in turn, would require studying more families with schizophrenia. "Due to the complex genetic characteristics of schizophrenia, it will likely be some time before the specific genes that are responsible will be identified and even longer before treatments based on these findings become possible," she said.
Members of the clinical team were: study chairman Ming Tsuang and Stephen Faraone from Harvard and, from the VA Medical Centers, Keith A. Young from Waco; Sarita Prabhudesai from Danville; Susan L. Haverstock from Augusta; Felicitas Mena from Tuskegee; A. Srikumar Menon from Perry Point; Fred Sautter from New Orleans; and Charlene Baldwin from Northport. Data management team members were David Weiss, Stephen Bingham and the staff of the VA Cooperative Studies Program Coordinating Center at Perry Point. The molecular genetics team consisted of Debby Tsuang and Gerard Schellenberg at the University of Washington and Tim Keith of Genome Therapeutics. The statistical genetics team includes Michael Boehnke and Andrew Skol of the University of Michigan.
The research was funded by the Department of Veterans Affairs, VA Merit Review and the VISN-20 Mental Research, Education and Clinical Center.
The American College of Neuropsychopharmacology (ACNP), founded in 1961, is a professional organization of some 600 leading scientists. Members are selected primarily on the basis of their original research contributions to the field of neuropsychopharmacology, which involves the evaluation of the effects of natural and synthetic compounds upon the brain, mind and human behavior. The principle functions of the College are research and education. ACNP's annual meeting is limited to participants from around the world who have made major research or clinical contributions in the field.