Gene may boost schizophrenia risk

Clues about how a suspect version of a gene may slightly increase risk for schizophrenia are emerging from a brain imaging study by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH). The gene variant produced a telltale pattern of activity linked to production of a key brain messenger chemical.

The study found that increased activity in the front of the brain predicted increases in the neurotransmitter dopamine in the middle of the brain in subjects with the suspected schizophrenia-related version of the gene. Yet, the opposite relationship held for subjects with the other of two common versions of the gene.

"A tiny variation in the gene that makes the enzyme that breaks down dopamine causes a complete flipflop – not a mere difference in degree – in dopamine activity in these two brain areas," explained NIMH's Dr. Andreas Meyer-Lindenberg, who, along with Dr. Karen Berman and colleagues, reported their findings in the April 10, 2005 online edition of Nature Neuroscience.

The NIMH study also for the first time confirms in living humans that activity of the front brain area, the prefrontal cortex, is regulated by dopamine production in the midbrain, which, in turn, is regulated by these two common gene variants.

Schizophrenia, a severe mental illness marked by hallucinations and delusions, affects one percent of the population and is treated with antipsychotic drugs that block dopamine. The prefrontal cortex is critical for motivation, learning in response to reward, and working memory – functions impaired in schizophrenia, which is thought to involve a dopamine imbalance.

Individuals inherit two copies (one from each parent) of the gene for the enzyme catecho-O-methyltransferase (COMT), which chemically breaks down dopamine. It comes in two versions, val and met, so a person can have two of the same version or one of each. Since it results in considerably weaker enzyme action, people with the met version are thought have more dopamine in their prefrontal cortex and perform better on tasks involving that part of the brain. Schizophrenia patients typically perform poorly on such tasks. Earlier studies had shown that inheriting two copies of the more common val version leads to a slightly higher risk for schizophrenia and a signature pattern of midbrain dopamine activity.

To see how the two gene versions affect the living human brain, the NIMH researchers scanned 24 healthy young adults twice using PET (positron emission tomography), which uses radioactive tracers to visualize brain function. The first scan measured subjects' overall brain activity while they performed working memory tasks. The second scan used a dopamine tracer to reveal the synthesis of the neurotransmitter in the midbrain.

Frontal cortex activity increased as midbrain dopamine activity increased in subjects with val, but decreased in those who had inherited two copies of the met COMT gene.

This "trait-like characteristic" of COMT gene type fits a model in which the prefrontal cortex functions optimally when dopamine activity is neither too low nor too high, corresponding to the top of an upside-down "U" (see diagram below). In this model, people with val fall on the left (rising) slope, with lower dopamine levels, while those with met fall on the right (falling) slope, with higher dopamine levels.

The findings suggest that dopamine "tunes" prefrontal neurons (brain cells) to achieve an optimal signal-to-noise ratio, much like a fine-tuning dial on a radio. For the clearest signal, the "dial" must be turned in opposite directions, depending on which version of the COMT gene one inherits: up with val, down with met. In people with val and schizophrenia, which is marked by too little prefrontal and too much midbrain dopamine, the dial is turned "way up," the NIMH researchers speculate.

"We expected that there would be different regulatory mechanisms between the two gene types, but it's amazing how well the data support this tuning model," said Berman. "The study is important for our understanding of schizophrenia because it clarifies the neural mechanism for a well-established risk gene."

Also participating in the NIMH brain imaging study were: Dr. Daniel Weinberger, Philip Kohn, Dr. Bhaskar Kolachana, Shane Kippenhan, NIMH; Dr. Aideen McInerney-Leo, Dr. Robert Nussbaum, National Human Genome Research Institute (NHGRI).