Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder

Abstract

The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

Fig. 1

Biological Markers (Known as Subclinical Traits or Vulnerability Markers) may be Primarily Environmental, Epigenetic, or Multifactoral and Then Origin. For this reason, criteria useful for the identification of endophenotypes, a special subset of such markers for studies in psychiatric genetics have been proposed, adapted, and refined over time (see ,,–30). Current criteria for an endophenotype, to be distinguished from biological markers, are designed to direct clinical research in psychiatry toward genetically and biologically meaningful conclusions. © 2005, I.I. Gottesman and used with permission.

Fig. 2

Gene Regions, Genes, and Candidate Endophenotypes are Implicated in a Biological Systems Approach to Schizophrenia Research. The reaction surface suggests the dynamic developmental interplay among genetic, environmental, stochastic, and epigenetic factors that produce cumulative liability to developing schizophrenia spectrum and schizophrenia disorders above each of the 2 thresholds shown. Endophenotypes are characterized by simpler neurobiological and genetics antecedents than psychiatric disorders. The schizophrenia phenotype, as an example, is associated with a number of candidate genes and chromosomal regions, the influence of which can be observed at the levels of either behavior or endophenotypes. Endophenotypes, located closer to genes in the pathway from genes to behaviors, have fewer genes associated, and thus are more amenable to genetic investigations and studies in model systems. This skeleton (genes to endophenotypes to behaviors), allowing for epigenetic, “environmental,” and purely stochastic influences upon clinical observations, and inspired by bioinformatics and the HapMap, can be applied to other diseases with complex genetics using the input of disease-specific candidate genes/regions, single nucleotide polymorphismss, and endophenotypes. None of the sections of this figure can be definitive; many more elements exist and await discovery (represented by “etc.” and question marks). © 2005, I.I. Gottesman and used by permission.

Fig. 3

This Figure Indicates the “Ease” of Defining the Genetic Architecture of Single Gene, Mendelian Dominant Disorders (eg, Huntington's) vs the More Daunting Task of Understanding the Genetic Architecture of Complex Disorders Such as Diabetes, Schizophrenia, Bipolar Disorder, and Hypertension.