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Arguments for the sake of endophenotypes: Examining common misconceptions about the use of endophenotypes in psychiatric genetics

Authors

  • David C. Glahn,

    Corresponding author
    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut
    • Correspondence to:

      David C. Glahn, Ph.D., Olin Neuropsychiatry Research Center, Whitehall Research Building, Institute of Living, 200 Retreat Ave, Hartford, CT 06106.

      E-mail: david.glahn@yale.edu

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  • Emma E.M. Knowles,

    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut
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  • D. Reese McKay,

    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut
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  • Emma Sprooten,

    1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    2. Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut
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  • Henriette Raventós,

    1. Centro de Investigación en Biología Molecular y Celular, Universidad de Costa Rica, San José, Costa Rica
    2. Escuela de Biología, Universidad de Costa Rica, San José, Costa Rica
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  • John Blangero,

    1. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
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  • Irving I Gottesman,

    1. Department of Psychology, University of Minnesota, Minneapolis, Minnesota
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  • Laura Almasy

    1. Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas
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  • Authors have no conflicts of interest to disclose.

Abstract

Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing, and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community. © 2014 Wiley Periodicals, Inc.

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