New Program Will Pursue Schizophrenia Gene Leads
The National Institute of Mental Health (NIMH), part of the National Institutes of Health (NIH), today announced a new program expanding genetics research on schizophrenia in its own Bethesda, Maryland laboratories.
"Recent discoveries in the genetics of schizophrenia offer us an unprecedented opportunity for progress in reducing the burden of this illness. For the first time, we have at least half a dozen vulnerability genes to explore," said NIMH Director Thomas Insel, M.D. "But finding a gene is just a starting point. The Institute's Intramural Research Program (IRP) is uniquely positioned to seize the opportunity and find out how these genes interact and how they affect developing brain systems for cognition and behavior."
"Pursuing high-risk and high-impact research and following up quickly on unanticipated leads is what the intramural program does best," added NIH Director Elias Zerhouni, M.D. "This new program builds on the outstanding schizophrenia research already in place to develop a multi-disciplinary effort for a serious public health problem."
Daniel Weinberger, M.D., chief, NIMH Clinical Brain Disorders Branch (CBDB), will direct the new program, which, over the next decade, will redouble intramural efforts focused on the genetics and neurobiology of cognition and psychosis. Multidisciplinary teams using mouse, fruit-fly and cell culture models, as well as clinical studies and brain imaging, will tease apart how the vulnerability genes work at the molecular, cellular and systems levels to discover the "risk architecture" of schizophrenia. Rather than relying on traditional clinical features of the illness, they will pursue changes in the brain underlying the altered thinking and emotionality associated with the illness.
"Genes don't directly encode for the hallucinations, delusions and blunted affect of schizophrenia," explained Weinberger. "Rather, there is a very complicated path between a gene's influence on the regulation and function of a protein and such psychiatric phenomena."
For example, Weinberger's group found a slightly increased risk for schizophrenia among people who inherit one of two common versions of the COMT gene, which codes for the enzyme that metabolizes neurotransmitters like dopamine and norepinephrine. The gene appears to bias the brain toward a pattern of neurochemical activity associated with psychosis and poorer performance on tasks requiring activation of the frontal lobe. NIMH brain imaging studies have consistently found that schizophrenia patients falter on such tasks and have problems activating that part of the brain.
Other genes currently regarded as candidates are: GRM3, DISC1, dysbindin and neuregulin. Each contributes about three to four percent of the variance in vulnerability to schizophrenia, according to Weinberger, who said postmortem studies in brains of people who had the illness have begun to demonstrate abnormalities in the expression of some of these genes. The new studies may identify biological tests and ways to turn-on or turn-off genes that could be developed into strategies for prevention or treatment of the illness.
"Such findings emerging from the fast-track intramural effort will serve to stimulate spin-off studies by extramural, or grant-supported, researchers," said Insel.
The plan tentatively calls for recruitment of at least seven new senior scientists, each of whom will head up teams composed of post-doctoral fellows and other support personnel. The schizophrenia program will also gain new laboratories on genetics and cell biology, a new MRI scanner, and an additional 8,200 square feet of new space on the NIH Bethesda campus, said NIMH IRP Director Robert Desimone, Ph.D., who assembled the resources to make the new effort possible. The initiative will boost NIMH intramural schizophrenia research by an additional $6 million annually.
Researchers will identify how variations in the chemical sequence of each gene affects its function. Using genetically engineered animals, they will explore the cellular mechanisms by which variations in the genes lead to deficits. A basic animal neurobiology team will test each gene variant for gene-gene and gene-environment interactions at the level of behavior, pharmacology, electrophysiology and molecular biology. Gene-gene interactions will also be studied at the level of clinical illness and brain information processing in humans, said Weinberger.
Ranking among the top 10 causes of disability in developed countries worldwide, schizophrenia affects one percent of the adult population, typically beginning in young adulthood, with hallucinations, delusions, social withdrawal, flattened emotions and loss of social and personal care skills. Evidence suggests that it is a neurodevelopmental disease, likely involving interaction of several genes, a prenatal insult to the developing brain, and stressful life events. The role of genetics has long been established; the risk of schizophrenia rises to 10 percent if a first degree relative has it, and to 50 percent if an identical twin has it.
An advisory panel of outside experts has been named to assist the intramural effort: Christopher Austin, M.D and Eric Green, Ph.D., National Human Genome Research Institute; David Goldman, M.D., National Institute on Alcohol Abuse and Alcoholism; Jeffrey Lieberman, M.D., University of North Carolina; Eric Nestler, M.D., University of Texas Southwestern Medical Center; Edward Scolnick, M.D., Merck Research Labs; Stephen Warren, Ph.D., Emory University; Tim Tully, Ph.D., Cold Spring Harbor Laboratory.
NIMH is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.