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Endophenotypes promise insight into Genetics of Schizophrenia.

NEW YORK -- Markers of discrete neuropsychological and neurophysiologic dysfunctions associated with schizophrenia--endophenotypes--represent a promising new research focus that may help disentangle the complex genetics of the disorder, Jeremy M. Silverman, Ph.D., said at a conference on schizophrenia sponsored by Columbia University.

Such traits as a defective ability to screen out irrelevant sensory stimuli are widespread in individuals with schizophrenia and occur at increased frequency among unaffected relatives who don't have the disorder. Each may reflect the expression of a single gene whose combined operation results in psychopathology, said Dr. Silverman, professor of psychiatry and director of the family studies research center at Mount Sinai School of Medicine, New York.

The presence of a genetic factor in schizophrenia is well documented by twin studies and adoption studies: Concordance rates are significantly higher among monozygotic than dizygotic twins, and prevalence of the disorder is higher among biologic than adoptive relatives of probands. Gene linkage and association studies have pointed to a handful of loci on different chromosomes. "But no locus has been replicated by a majority of groups. We know genetics plays an important role, but we haven't really identified any genes," Dr. Silverman said at the meeting, which was cosponsored by the New York State Psychiatric Institute.

It seems highly likely that schizophrenia is polygenic. The clinical disorder is the result of several genes, each tied to a specific deficit, operating together.

The Consortium on the Genetics of Schizophrenia represents an effort to tease out those interwoven strands. The seven-center initiative focuses on traits, identifiable by laboratory testing, that may reflect the operation of individual genes.

"Endophenotypes are midway between gene and clinical disorder. They more directly show the effect of the gene," Dr. Silverman said.

The endophenotypes under investigation include attention, as measured by the continuous performance task; working and verbal memory; and neurophysiologic parameters such as prepulse inhibition of the startle response and antisaccade eye movement, an index of the ability to avoid distraction.

Dr. Silverman described one area of investigation, P50 suppression, in some detail. What is measured here is a brain wave generated 50 microseconds after the subject hears a click through a headset. A repetition of the click 500 microseconds later generates an attenuated version of the same wave.

The phenomenon apparently reflects "sensory gating," a filter mechanism that selects among auditory and visual stimuli of greater and less importance. It may be that the filter mechanism is less functional in people with schizophrenia, he said.

For normal subjects, the amplitude of the response to the second click is reduced by 80%, but in 85% of individuals with schizophrenia, it is reduced by less than half.

This "nonsuppression" trait has also been found in half of clinically unaffected first-degree relatives of people with the disorder.


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Title Annotation:Adult Psychiatry
Author:Sherman, Carl
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:May 1, 2004
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