Doctors have long known schizophrenia has a genetic basis, and have hypothesized that the disease resulted from combinations of common genes, or alleles, each contributing towards the disease in a small way. But a new study, co-authored by a Case Western Reserve University School of Medicine faculty member, suggests that a predisposition to schizophrenia may instead be caused by just a few, rare genetic mutations, each contributing significantly to the disease.
The study, "Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia," has been published in the April 2008 issue of Science magazine. Robert Findling, M.D., the Rocco L Motto, M.D. Professor of Child & Adolescent Psychiatry at the Case Western Reserve University School of Medicine, and director of Child & Adolescent Psychiatry at Case Medical Center, a partnership between the university's School of Medicine and University Hospitals, is a co-author.
"We present a model which states there may be some genetic mutations that are rare, but when present, they are associated with substantially increased risk of being predisposed to developing schizophrenia This is very different from the 'common disease-common allele' model currently in use," Findling explained.
The studies further revealed those under the age of 18 with the mutations showed a particularly strong predisposition to schizophrenia compared adults. This is important, Findling said, because "if youngsters are overrepresented, or expressing mutations more commonly than would otherwise be expected, in these groups with these rare but highly significant genetic differences, it means there may be specific genes that are associated with variability in long-term outcomes. It really highlights a different means of thinking about genetic studies of schizophrenia."
Findling was the Case Western Reserve University site's principal investigator on the four-site National Institute of Mental Health (NIMH)-supported Treatment for Early Onset Schizophrenia Spectrum (TEOSS) study.
Considered one of the most debilitating of neuropsychological diseases, schizophrenia currently affects about one percent of the world's population. While it can strike individuals of any age, it is more difficult to treat, and its outcomes are worse, when it occurs among children and adolescents.
Researchers compared the frequency of microdeletions or microduplications of genes—also known as structural variants—occurring in groups of individuals with schizophrenia with those in control groups. Previous studies found structural variants to be the underlying cause of many serious illnesses, including neurological and neurodevelopmental syndromes.
The current study found that those with schizophrenia were more than three times as likely to have structural variants as the group without the disease. Among individuals where the disease first appeared at age 18 or younger, the rate was four times greater. By contrast, there was no significant difference between the two groups when the mutations did not affect any genes.
A second part of the study, looking just at patients with childhood onset schizophrenia (COS), also found a significantly higher proportion of structural variants among the children as compared to their parents.
Researchers next sought to determine a specific relationship between genes disrupted by variants and schizophrenia. They found that the affected genes in the patient groups with schizophrenia were significantly overrepresented in pathways that are particularly important for brain development, especially signaling networks controlling neurodevelopment. The disrupted genes in the control group patients were not overrepresented in any pathway.
The TEOSS study's methods and the baseline characteristics of the patients appeared in the Journal of the American Academy of Child and Adolescent Psychiatry in August, 2007.
Findling said the Discovery and Wellness Center for Children (DWCC) is conducting other treatment studies among children and adolescents with schizophrenia. "These studies are part of our mission of understanding and treating youngsters who suffer from serious psychiatric conditions," he explained.
Findling and colleagues are currently recruiting youngsters suffering from a variety of psychiatric conditions for possible participation in ongoing studies, some of which involves treatment research. For more information about the DWCC and its studies, call (216) 844-3922.
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