National Institute of Mental Health scientists have linked a gene variant that reduces dopamine activity in the prefrontal cortex to poorer performance and inefficient functioning of that brain region during working memory tasks, and to slightly increased risk for schizophrenia. The finding, which must still be confirmed by independent teams of investigators, emerged from an ongoing study of people with schizophrenia and their siblings. The study is among the first to suggest a mechanism by which a gene might confer

susceptibility to a mental illness, say the researchers. Daniel Weinberger, M.D., Michael Egan, M.D., NIMH Clinical Brain Disorders Branch, and colleagues, report on their results in the May 29, 2001 "Proceedings of the National Academy of Sciences".

The most disabling form of mental illness, schizophrenia affects one percent of the adult population, typically in young adulthood, with hallucinations, delusions, social withdrawal, flattened emotions and loss of social and personal care skills. Although its cause remains a mystery, evidence suggests that it is at least 80% heritable, stemming from complex interactions among several genes and non-genetic influences. Several chromosomal regions have been implicated, but none have been definitely confirmed and no genes have yet been linked to the disorder.

Given the syndrome's daunting complexity, Weinberger and colleagues have been studying many traits to identify those that patients share with their well siblings, hoping to turn up clues to susceptibility genes. Their brain imaging studies had revealed that both well siblings and patients falter on tasks of working memory and show abnormal activation of the prefrontal cortex, which is required for such "executive" functions. Studies have shown that the chemical messenger dopamine plays a pivotal role in tuning the activity of the prefrontal cortex during such tasks.

A gene called COMT (catecho-o-methytransferase) had long been suspected of being involved because it codes for an enzyme that breaks down dopamine after it is secreted into the synapse. People inherit two copies of COMT (one from each parent), each in either of two forms. The most common variant, "val", reduces prefrontal dopamine activity, while a somewhat less common form, "met", increases it.

Weinberger and colleagues administered a working memory task known to activate the pre-frontal cortex, the Wisconsin Card Sorting Test (WCST), to 181 schizophrenia patients, 219 of their well siblings and 75 normal controls. They found that those who had inherited 2 copies of "val", on average, performed worse than those with only one copy. Those with two copies of "met" performed best. COMT accounted for 4.1% of the variance in test performance among patients and controls, suggesting that it influences prefrontal functioning

When healthy siblings were asked to perform another working memory task (N-back) while undergoing functional magnetic resonance imaging (fMRI) (http://www.nimh.nih.gov/hotsci/mri.htm), the prefrontal brain activity of those with two copies of "val" was least efficient; there was excessive activity for a given level of performance.

"It's as if they get poorer gas mileage out of their prefrontal cortex if they have this genetic background," said Weinberger, who led the research team. Brain activity of those with one copy of each variant was more efficient, while activity of siblings who inherited two copies of "met" showed the highest brain efficiency, on average.

Among 104 pairs of parents studied, the investigators discovered that the "val" form of COMT was transmitted to offspring who eventually developed schizophrenia more often than would be expected by chance: 75 times for "val", compared to 51 times for "met". Inheriting two copies of the "val" form accounts for a 1.5-fold increased risk for schizophrenia in the general population.

The researchers suspect that COMT's effect, while modest, may be amplified through interaction with other susceptibility genes and environmental factors. For example, they are studying a gene in the brain's hippocampus that, together with COMT, could boost schizophrenia risk three-fold.

Although it's not yet known exactly how the COMT "val" variant impairs prefrontal efficiency, evidence suggests that by reducing dopamine it reduces signal-to-noise ratios of communications between neurons, much like static drowns out weak radio stations.

"The COMT "val" allele is certainly not a necessary or sufficient causative factor for schizophrenia, nor is it likely to increase risk only for schizophrenia," caution the researchers. "However, its biological effect on prefrontal function and the relevance of prefrontal function for schizophrenia implicate a mechanism by which it increases liability for the disorder."

The researchers are planning to study a COMT inhibitor medication as a possible adjunct treatment to enhance cognitive performance in patients with the "val" variant. There is evidence that current anti-psychotic drugs work by blocking D2 dopamine receptors in lower dopamine circuits. The NIMH researchers propose that the COMT inhibitor will specifically enhance dopamine circuits specific to the prefrontal cortex.

Also participating in the study were Terry Goldberg, Ph.D, Bhaskar Kolachan, Ph.D., Joseph Callicott, M.D., NIMH Clinical Brain Disorders Branch; and David Goldman, M.D., Chiara Mazzanti, Ph.D., Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism.

The National Institute of Mental Health (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