The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia

Abstract

Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.

Figure 1.. Genetic architecture of complex disorders. This illustrates a major conundrum of research into complex human disorders. The Huntington's gene was identified 20 years ago, but has not yet led to a genetic “cure.” The profoundly important potential of genetic treatments for even more “complex genetic disorders” (eg, schizophrenia, hypertension, and diabetes) will depend on related scientific advances.

Figure 2.. The vulnerability-stress 2-hit model of schizophrenia. “High” levels of vulnerability interacting with high levels of stressors (eg, neonatal hypoxema or adolescent stimulant abuse) may “evoke” the emergence of schizophrenia. Despite the view of schizophrenia as a “genetic disorder,” 50% of causation is genetic and 50% or so of the disorder is caused by “nongenetic” second hits.

Figure 3.. The effects of a loss of normal gating. In the left panel, an individual with intact filtering and inhibition filters out irrelevant sensory stimuli. In the right panel, impaired gating leads to a sequence of sensory inundation, cognitive fragmentation, and disorganized thinking.

Figure 4.. Prepulse inhibition (PPI) is a profound decrease in startle response magnitude when the startling pulse is preceded by a weak prepulse. PPI is an operational measure of sensorimotor gating.

Figure 5.. Zuditory click pairs are presented to subjects; the electroencephalogram (EEG) is averaged across trials. The P50 component of the averaged event-related potential (ERP) is measured in response to the first and second clicks. The percentage of P50 amplitude reduction from the first to the second click is referred to as P50 suppression or P50 gating, and is considered an operational measure of sensory gating. Deficient P50 suppression is often seen in patients with schizophrenia, their clinically unaffected family members, and individuals with schizotypal personality disorder.