Teens with missing part of a chromosome confirm genetic role in schizophrenia

A study in youth who are missing part of a chromosome is further implicating a suspect gene in schizophrenia.

Youth with this genetic chromosomal deletion syndrome already had a nearly 30-fold higher-than-normal risk of schizophrenia, but those who also had one of two common versions of the suspect gene had worse symptoms. They were more prone to cognitive decline, psychosis and frontal lobe tissue loss by late adolescence, when schizophrenia symptoms begin to emerge, found the study, which was funded by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH) and the National Institute on Child Health and Human Development (NICHD).

The gene version appeared to worsen symptoms of the deletion syndrome by chronically boosting the chemical messenger dopamine to excessive levels in the brain's executive hub, the prefrontal cortex, during development. The study is the first to show the long-term effects of the dopamine-regulating gene in a disorder related to schizophrenia, say Drs. Allan Reiss, Doron Gothelf, Stanford University, and colleagues at the University of Geneva, who report on their findings in the November 2005 issue of Nature Neuroscience.

"It's not that there's a good or bad version of this gene," explained NIMH director Thomas Insel, M.D. "Either version can be an accomplice, via interactions with other genes and environmental factors, in creating a dopamine imbalance that disturbs information processing. In this case, one version conspired with a rare mutation to produce too much dopamine. In other cases, the other version may tip the balance in the opposite direction."

Antipsychotic drugs used to treat schizophrenia work, in part, by correcting a dopamine imbalance in the prefrontal cortex, seat of motivation, learning in response to reward, and working memory -- functions impaired in schizophrenia. Previous studies have found – and the current study confirms – that optimal cognitive functioning depends on a "narrow window" of dopamine activity there, note the researchers.

While most people inherit two copies of the gene for the enzyme that breaks down dopamine, one in 4000 children are born with just one copy of the catecho-O-methyltransferase (COMT) gene. The gene is located in the tiny part of chromosome 22 that is partly missing in the 22q11.2 deletion syndrome, also known as the velocardiofacial syndrome. A mutation causes a variable array of problems, including cleft palate, heart defects and cognitive deficits.

Since about 30 percent of people with the chromosomal deletion syndrome also develop schizophrenia or related psychotic disorders – compared to only one percent of the general population – Reiss and colleagues suspected that people with the syndrome may hold unique clues about how the COMT gene influences development of the mental disorder.

A variation in the COMT gene's sequence results in two common versions: val and met – one version produces an enzyme that has the amino acid valine in the same position as the other has a methionine. The val version results in stronger COMT enzyme activity. For example, people who inherit two copies of val have 40 percent higher prefrontal cortex enzyme activity, resulting in more rapid chemical breakdown and markedly lower dopamine levels than people with two copies of met.

In some studies, val has been associated with slightly increased risk for schizophrenia, but evidence now suggests that either version can potentially increase risk, depending on how prefrontal dopamine is affected by interactions with other genes and environmental events. Since people with the deletion syndrome carry only one copy of the COMT gene, their enzyme activity is already compromised. If that copy is a met, its weak enzyme action would likely expose their developing brains to excessive, potentially damaging prefrontal dopamine levels, with attendant adverse consequences, hypothesized the researchers at Stanford's Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences.

To find out, they followed 24 subjects with the deletion syndrome and 23 matched control subjects with developmental disabilities. When first tested in childhood, subjects with the syndrome and met did not suffer from psychotic disorders and performed cognitive tasks as well or better than subjects with val. Yet, when they were re-tested in late adolescence/early adulthood, seven (29.2 percent) subjects with the syndrome had developed schizophrenia or other psychotic disorders, compared to only one from the developmental disabilities group. The syndrome group showed significant declines in tests of verbal IQ, and expressive language. Subjects with met showed more robust decreases on these measures, as well as more severe psychotic symptoms, and more loss of prefrontal cortical gray matter volume than subjects with val.

The researchers propose that dopamine increases that normally occur during adolescence are further boosted in syndrome-affected teens with met, leading to "reduced efficiency of cognitive processing" during adolescence.

Reiss and colleagues say their results fit a pattern seen in NIMH studies in which the relationship between prefrontal cortex function and dopamine levels are modeled on an inverted "U"-shaped curve, the top of which represents optimal cognitive functioning. In this case, the double jeopardy of having the deletion syndrome and met would shift subjects' functioning well to the right, onto the down slope of the inverted "U" curve. Much like dialing-in a radio station, dopamine levels need to be precisely tuned – not too much or too little – to maximize the signal and minimize the noise, so that the prefrontal cortex can efficiently process information. In this case, it is as if the dial is turned too far clockwise, tuning-in too much static and not enough of the station's signal.

The Stanford researchers suggest that other genes in the deletion area likely also play a role in the development of psychotic and cognitive symptoms.



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