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Prefrontal Coexpression of Schizophrenia Risk Genes Is Associated With Treatment Response in Patients

  • Author Footnotes
    1 GP and PDC contributed equally as first authors.
    Giulio Pergola
    Correspondence
    Giulio Pergola, PhD, Piazza G Cesare, 11, 70124 Bari, Italy.
    Footnotes
    1 GP and PDC contributed equally as first authors.
    Affiliations
    Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Author Footnotes
    1 GP and PDC contributed equally as first authors.
    Pasquale Di Carlo
    Footnotes
    1 GP and PDC contributed equally as first authors.
    Affiliations
    Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Andrew E. Jaffe
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland

    Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

    Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

    Center for Computational Biology, Johns Hopkins University, Baltimore, Maryland
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  • Marco Papalino
    Affiliations
    Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
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  • Qiang Chen
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Thomas M. Hyde
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Joel E. Kleinman
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland

    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Joo Heon Shin
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
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  • Antonio Rampino
    Affiliations
    Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy
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  • Giuseppe Blasi
    Affiliations
    Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy
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  • Daniel R. Weinberger
    Affiliations
    Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland

    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Alessandro Bertolino
    Correspondence
    Address correspondence to Alessandro Bertolino, M.D., Ph.D., Piazza G Cesare, 11, 70124 Bari, Italy
    Affiliations
    Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy
    Search for articles by this author
  • Author Footnotes
    1 GP and PDC contributed equally as first authors.

      Abstract

      Background

      Gene coexpression networks are relevant to functional and clinical translation of schizophrenia risk genes. We hypothesized that schizophrenia risk genes converge into coexpression pathways that may be associated with gene regulation mechanisms and with response to treatment in patients with schizophrenia.

      Methods

      We identified gene coexpression networks in two prefrontal cortex postmortem RNA sequencing datasets (n = 688) and replicated them in four more datasets (n = 1295). We identified and replicated (p values < .001) a single module enriched for schizophrenia risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the schizophrenia risk module via bioinformatic analyses identified two transcription factors and three microRNAs associated with the risk module. To translate postmortem information into clinical phenotypes, we identified polymorphisms predicting coexpression and combined them to obtain an index approximating module coexpression (Polygenic Coexpression Index [PCI]).

      Results

      The PCI-coexpression association was successfully replicated in two independent brain transcriptome datasets (n = 131; p values < .05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with schizophrenia treated with olanzapine (n = 167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (p values < .05).

      Conclusions

      In summary, our findings in 1983 samples of human postmortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This coexpression pathway may be coregulated by transcription factors and microRNA associated with it.

      Keywords

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