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, brainbased deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, traitrelated 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 secondgeneration 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.

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

“…Third, a number of endophenotypes have been proposed (Table 2), often based on physiologic measures of information processing. This is especially critical in the post-genomic era since genotype/endophenotype relations are likely to be far more robust than genotype/ schizophrenia relations (Braff and Light, 2005;Braff et al, 2007;Thaker, 2007). Here too, facilitation of animal (Table 3) and human experimental models useful in drug development are promising so long as phenotypes can be translated from one species to the other.…”

“…The current status in these fields has been explored in recent NIMH workshops (Buchanan et al, 2005;Geyer and Heinssen, 2005;Kirkpatrick et al, 2006). New knowledge on genotype/endophenotype relationships will create another paradigm in which to conceptualize novel drug development (Braff and Light, 2005;Braff et al, 2007;Thaker, 2007).…”

Genetic epidemiology, endophenotypes, and eating disorder classification

“…4 However several significant advantages emerge from the identification of endophenotypes, including deconstruction of complex disorders 10 that could theoretically assist in developing a more biologically based and homogenous classification system for eating disorders. 11 Refining endophenotypes for eating disorders may assist with identifying core, genetically influenced traits that inform the underlying scaffolding around which the diagnostic criteria for eating disorders should be constructed.…”

Advances in endophenotyping schizophrenia

“…In this context, Steps 1-3 may take 10 to 20 years to refine, test, replicate and provide a viable platform for the family and genetic studies that follow (3). Once a familial-transmitted endophenotype is identified, it is of interest to see if it co-segregates with the disorder itself.…”