In new research that helps to reveal the nature of schizophrenia at the cellular level, UCLA scientists report the discovery of unique DNA sequence variations associated with increased risk for schizophrenia, impairments in short- and long-term memory, and other cognitive deficits.
"I hope this is the opening salvo in a new molecular approach to fighting schizophrenia," said Tyrone D. Cannon, UCLA's Staglin Family Professor of Psychology, Psychiatry and Human Genetics. "If we're able to identify people at risk for the illness through sequence variations in genes and know what biochemical pathways are affected by those variations, we're much closer to the day when we can finally prevent schizophrenia."
Cannon and his colleagues report unique genetic variations on chromosome 1, the largest human chromosome, in two regions of a gene known as DISC1, that are predictive of schizophrenia, neurocognitive deficits, memory impairment, and reductions of gray matter density in the brain's frontal lobes and hippocampus. They found sequence variations within the DISC1 gene that relate to features associated with the underlying neural basis for schizophrenia.
The research is published in the November issue of the Archives of General Psychiatry, the leading journal in psychiatry and psychopathology.
Cannon and his colleagues identified a sequence variation -- in a region partly in DISC1 and partly in the neighboring TRAX gene -- that occurs in only 1 percent of the population, but in 10 percent of schizophrenia patients, who have the nucleotide sequence "A, A, T, G," rather than the healthy version, "C, C, T, G." People with this sequence abnormality have significantly reduced gray matter in the frontal cortex, part of the brain implicated in schizophrenia, said Cannon, who is director of UCLA's Staglin Family Music Festival Center for the Assessment and Prevention of Prodromal States, and of UCLA's Center for Cognitive Neuroscience.
"If you have that sequence, your risk for having schizophrenia is greatly increased, by a factor of 10," Cannon said.
He offers an analogy to illustrate the progress of the research:
"A crime has been committed, and the SWAT team has encircled the neighborhood, which is DISC1," Cannon said. "Now we have identified the address and we think we have found the murder weapon. It's only a matter of time before we have the suspect handcuffed on the lawn."
"The genetics of schizophrenia has progressed much more rapidly in the last two or three years than it had in the prior 50," added Cannon, who is also a research scientist at the UCLA Semel Institute of Neuroscience and Human Behavior.
The researchers studied more than 230 twins in Finland. In some of the pairs, both twins have schizophrenia; in others, one has schizophrenia; and in half of the twins, neither has schizophrenia. The researchers analyzed their DNA, conducted MRI scans and used three-dimensional brain mapping techniques.
"We have identified particular sequence variations that could be genotyped in any individual," said Cannon, who is hopeful the research will lead to a treatment that could fix the protein. For example, it is possible that turning "A, A, T, G" to the healthy "C, C, T, G" sequence would result in a normally functioning DISC1 protein, he said.
While schizophrenia patients appear not to have fewer neurons in the brain, the neurons make fewer and weaker connections in regions that synthesize information, Cannon said.
"DISC1 is a strong candidate for explaining some of the cellular pathology that we see in postmortem studies, that in turn appears as reduced gray matter on MRI scans," he said. "This gene participates in the development and maintenance of synaptic connectivity in the frontal brain region that is very important for integrated cognition.
"We're showing that a fundamental mechanism is broken for producing the connectivity between brain cells," Cannon added. "This suggests that in schizophrenia patients, their brain plasticity is broken. This is a different way of thinking about the illness at the cellular level."
In his crime analogy, the murder weapon is how DISC1 adversely affects "neural scaffolding" and results in a reduction of connectivity between brain cells.
Future research goals include confirming that the genetic variation affects the cellular connectivity in the brain, and discovering whether that cellular connectivity can be rescued.
DISC1 is a susceptibility gene for schizophrenia, and there are probably several others that have yet to be identified, Cannon said.
Co-authors on the Archives of General Psychiatry study include Leena Peltonen, a molecular geneticist at the National Public Health Institute in Finland, and founding chair of the department of human genetics at UCLA's David Geffen School of Medicine; Arthur Toga, professor of neurology, co-director of the Division of Brain Mapping at UCLA's David Geffen School of Medicine, and director of the Laboratory of Neuro Imaging; and Paul Thompson, associate professor of neurology at UCLA's David Geffen School of Medicine. The research was funded by the National Institute of Mental Health and the Staglin Family Music Festival for Mental Health.
Cannon led a team of UCLA scientists who in 2002 reported using a novel three-dimensional mapping technique to identify regions of the brain where people with schizophrenia have significantly less gray matter than their identical twins and the rest of the population. Schizophrenia patients have significant reductions of gray matter in regions of the brain that integrate, interpret and organize information, Cannon and his colleagues reported in the Proceedings of the National Academy of Sciences (March 5, 2002).
In previous research, Cannon has identified the fundamental importance of genetic factors, showing that schizophrenia is more than 80 percent genetic, and that the environmental influences most likely depend on genetic factors as well.
Slightly more than 1 percent of the population is afflicted by schizophrenia, including more than 2 million Americans. Males typically get schizophrenia in their late teenage years, and females in their early 20s.
The symptoms of schizophrenia include hallucinations, delusions, hearing voices, disordered thinking, unusual speech and behavior, and social withdrawal. Seventy percent of patients hear voices, typically making derogatory comments about them, in the third person. Patients commonly have delusions, often involving persecution. Their thinking and speech are disorganized, and they may have a greatly reduced interest in social activities, and a reduced energy level. The earliest signs include sleep disturbance, depressed moods and declines in school functioning.
Through UCLA's Staglin Family Music Festival Center for the Assessment and Prevention of Prodromal States, Cannon and colleagues are working to prevent and detect schizophrenia in its early stages, as well as other psychotic illnesses, including bipolar disorder. (The word "prodromal" refers to the period immediately prior to the onset of psychosis and is marked by behavioral, cognitive and social deterioration.)
"I envision a day when schizophrenia ceases to be a debilitating disease," Cannon said. "Our goal is effective early intervention. Our psychological and pharmacological interventions are designed to reduce the likelihood of an initial psychotic episode, decrease the severity and chronicity of psychotic illness, and increase social functioning and the likelihood of stable employment."
The center performs screening evaluations and enrolls patients in research studies, offering preventive treatment free of charge to patients and their families, as the cost of treatment is underwritten by the Staglin family.
The center is looking for individuals ages 12-35 who are experiencing recent changes in their thoughts, feelings and behavior, such as unusual thoughts, distorted or heightened perceptions, ideas of special identity or abilities, suspiciousness, or odd behavior. Other changes may include reduced concentration, reduced energy, depressed mood, sleep disturbance, withdrawal from family or friends, trouble with work or school, anxiety, or irritability. Individuals who are experiencing difficulty functioning and who have a first-degree family member with a psychotic illness, such as schizophrenia, are also encouraged to contact the center. To receive more information, call the center at (310) 206-3466.
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