Abstract

Schizophrenia is not inherited because of a deficit in a single gene. Multiple genes appear to be involved in its inheritance, in addition to environmental factors. Because most analyses of genetic effects can be performed on only one gene at a time, gene hunting in schizophrenia becomes a risky business, fraught with uncertainties in research design and analytical conundrums. One way to determine the genetic architecture of schizophrenia is the endophenotype strategy illustrated by articles in this issue of the Journal from Hall et al. and Gur et al. This strategy investigates the genetic basis of subclinical endophenotypes, each of which is hypothesized to reflect more directly the effect of a specific gene than the illness itself (1). The illness is then conceptualized as the product of the interaction of multiple genetically influenced endophenotypes, along with environmental factors. Of course, the ultimate endophenotypes are perturbed levels of specific proteins or gene expression induced by inherited DNA sequence variations. This level of analysis is not yet possible in schizophrenia. Therefore, investigators turn to neurophysiological and neurocognitive measures that would seem to reflect more elementary aspects of the biology of the illness than the clinical features themselves. For example, poor