Specific information processing abnormalities and brain-related circuit dysfunction in schizophrenia patients may be the keys to finding the genetic basis of this puzzling, devastating mental illness that affects more than two million Americans and one percent of the world's population.

Scientists believe multiple genes cause schizophrenia, but specifically, the genetic basis of this disorder remains somewhat of a mystery. Research has pointed to several chromosomes that harbor likely disease-causing genes, but the search has been unsuccessful for the exact genetic code that causes this devastating, but elusive disorder.

Now, with a $20-million, five-year grant from the National Institute of Mental Health, seven academic research centers in the U.S., led by the University of California, San Diego (UCSD) School of Medicine, are taking a different approach to uncover the genetic causes of schizophrenia. Rather than starting with the broadly defined disorder itself, scientists are beginning with specific physiological markers, or traits, that are characteristic of schizophrenia in both patients and some clinically unaffected, normal family members. These physiological markers - caused by defects in brain circuits - will then be used to identify the complex genetic abnormalities that cause them.

"I believe our research is an important step in furthering our understanding of schizophrenia and then identifying the critical, genetically mediated brain dysfunctions that contribute to the disease," said David Braff, M.D., UCSD professor of psychiatry and director of the seven-center Consortium on the Genetics of Schizophrenia (COGS). "Instead of exploring the genetics of schizophrenia, we're identifying the genetics of different neurological deficits that occur in schizophrenia patients. "

He added that the main research hypothesis is based on the tenants of molecular biology. "If there are several different genetic abnormalities associated with schizophrenia, then each of them would cause a change in a specific protein. We believe that the series of protein changes in this disease is reflected by corresponding discrete functional abnormalities, such as disorganized thought processes," Braff said.

This strategy has been used for gene discovery in other complex medical illnesses. For example, in a form of colon cancer, researchers were able to identify a gene that causes multiple polyp formation, which leads to the cancer, rather than finding a gene for the cancer, itself.

At least six specific schizophrenia traits, called endophenotypes, will be studied in more than 2,000 individuals. UCSD, which is leading the project, will be joined by researchers at Harvard, Mt. Sinai School of Medicine, UCLA, University of Colorado Health Sciences Center, University of Pennsylvania and University of Washington, Seattle. Key to the studies will be the testing of individuals with schizophrenia and their clinically unaffected family members. These family members may have the same liability genes and associated traits, but are normal and don't show clinical signs of the disease. Specifically, the researchers will study cognitive dysfunction and abnormalities in perception and information processing experienced by schizophrenia patients. (See below for descriptions of tests.)

For example, schizophrenia patients, family members and "normal" individuals will be tested for deficits in the ability to inhibit, or "gate" irrelevant stimuli. People are constantly bombarded with a multitude of external and internal stimuli, and most individuals are able to select those stimuli that are most relevant to current activities and goals, while screening out - or gating - irrelevant stimuli. Schizophrenia patients are unable to filter the trivial from essential information and stimuli in everyday sensory input. They, therefore, have troubles navigating in everyday life activities because they are easily distracted, confused, and they become disorganized.

The disordered thinking that is characteristic of schizophrenia may be manifested in some of the more visible features of the disease, such as disorganization of speech and behavior with associated disabilities in work and social relationships.

"Ultimately, the COGS study will lead to a better understanding of the genetic abnormalities associated with these cognitive and information processing dysfunctions in schizophrenia patients," Braff said. "On a longer term basis, this functional genetics approach may lead to a new era of genetically informed treatment options. Thus, medications will be aimed at reversing genetically mediated brain dysfunctions and restoring schizophrenia patients to better levels of social and work function as their symptoms are alleviated."