It's as if they get poorer gas mileage out of their prefrontal cortex if they have this genetic background

Daniel Weinberger

The genetic variation leads to lowered dopamine activity in the brain's prefrontal cortex - the region responsible for memory. This leads to poorer brain performance.

The finding, which must still be confirmed, emerged from a study involving memory tests of people with schizophrenia and their well siblings.

Mystery illness

Schizophrenia affects 1% of the adult population, typically in young adulthood. Symptoms include hallucinations, delusions, social withdrawal and loss of social skills.

Its cause is a mystery, but some evidence suggests that it is chiefly heritable, though with strong environmental factors.

Several chromosomal regions have been implicated with the disorder, but no genes have yet been definitely linked to it.

Some scientists suspect that the chemical messenger dopamine is in some way responsible. Dopamine plays a crucial role in the brain's activity.

Suspect gene

A gene called COMT (catecho-O-methytransferase) is also suspected of being involved because it produces an enzyme that breaks down dopamine after it is secreted in the brain.

People inherit two copies of COMT (one from each parent). It comes in one of two forms. The most common variant, 'val', reduces dopamine activity in the prefrontal cortex, while the somewhat less common form, 'met', increases it.

To investigate the relationship between these gene variants, brain activity and schizophrenia, Daniel Weinberger and colleagues from the National Institutes for Mental Health, US, conducted brain imaging studies on sufferers and their relatives.

They found that their COMT genes influenced the brain's efficiency in the prefrontal cortex region, the area of the brain that plays an important role in memory.

They asked patients to perform memory exercises known to activate the prefrontal cortex. They found that those who had inherited two copies of 'val', performed worse, on average, compared with those who have only one copy. Those with two copies of 'met' performed best.

The researchers discovered that when healthy siblings of schizophrenia sufferers were asked to perform another memory task while undergoing a brain scan, the prefrontal brain activity of those with two copies of 'val' was least efficient; there was excessive brain 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 Dr Weinberger.

Among the 208 people studied, the investigators discovered that those who inherited two copies of the 'val' form had a 1.5-fold increased risk for developing schizophrenia.

'Increased liability'

The researchers suspect that COMT's effect, while modest, may be amplified through interaction with other as yet undiscovered susceptibility genes and environmental factors.

For example, they are studying a gene active in the brain's hippocampus that, together with COMT, could boost schizophrenia risk three-fold.

It is not yet known exactly how the COMT 'val' variant impairs prefrontal efficiency. The evidence suggests that by reducing dopamine it reduces the ability of neurons to communicate efficiently.

"By itself the COMT 'val' gene is certainly not a necessary or sufficient causative factor for schizophrenia, nor is it likely to increase risk only for schizophrenia," the researchers write in a paper published in the journal, Proceedings of the National Academy of Sciences.

"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."