The utility of P300 as a schizophrenia endophenotype and predictive biomarker: Clinical and socio-demographic modulators in COGS-2

Bruce I. Turetsky, Erich M. Dress, David L. Braff, Monica E. Calkins, Michael F. Green, Tiffany A. Greenwood, Raquel E. Gur, Ruben C. Gur, Laura C. Lazzeroni, Keith H. Nuechterlein, Allen D. Radant, Larry J. Seidman, Larry J. Siever, Jeremy M. Silverman, Joyce Sprock, William S. Stone, Catherine A. Sugar, Neal R. Swerdlow, Debby W. Tsuang, Ming T. TsuangGregory Light

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test-retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results.

Original languageEnglish
Pages (from-to)53-62
Number of pages10
JournalSchizophrenia Research
Issue number1-3
StatePublished - 1 Apr 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier B.V.


This work was supported by collaborative R01 grants from the National Institute of Mental Health : MH065571 , MH065707 , MH065554 , MH065578 , MH065558 , MH86135 . Other than providing financial support, the NIMH had no further role in this manuscript. Dr. Lazzeroni is an inventor on a patent application filed by Stanford University on genetic polymorphisms associated with depression. Dr. Light has served as a consultant for Astellas, Forum, and Neuroverse. Dr. Nuechterlein has received unrelated research support from Janssen Scientific Affairs, Genentech, and Brain Plasticity, Inc., and has consulted to Genentech, Otsuka, Janssen, and Brain Plasticity, Inc. Dr. Swerdlow has been a consultant for Genco Sciences, Ltd. All other authors declare that they have no conflict of interest.

FundersFunder number
National Institutes of Health
National Institute of Mental HealthMH065558, R01MH086135, MH065554, MH065578, MH065571, MH065707
Janssen Pharmaceuticals
Janssen Scientific Affairs


    • Biomarker
    • Endophenotype
    • Event-related potential
    • P300
    • Schizophrenia


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