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Sex Differences in the Human Brain Transcriptome of Cases With Schizophrenia

  • Author Footnotes
    1 GEH and YM contributed equally to this work.
    Gabriel E. Hoffman
    Correspondence
    Address correspondence to Gabriel E. Hoffman, Ph.D.
    Footnotes
    1 GEH and YM contributed equally to this work.
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 GEH and YM contributed equally to this work.
    Yixuan Ma
    Footnotes
    1 GEH and YM contributed equally to this work.
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Kelsey S. Montgomery
    Affiliations
    Sage Bionetworks, Seattle, Washington
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  • Jaroslav Bendl
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Manoj Kumar Jaiswal
    Affiliations
    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York

    Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, New York
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  • Alex Kozlenkov
    Affiliations
    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York

    Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, New York
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  • Mette A. Peters
    Affiliations
    Sage Bionetworks, Seattle, Washington
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  • Stella Dracheva
    Affiliations
    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York

    Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, New York
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  • John F. Fullard
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Andrew Chess
    Affiliations
    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Bernie Devlin
    Affiliations
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Solveig K. Sieberts
    Affiliations
    Sage Bionetworks, Seattle, Washington
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  • Panos Roussos
    Correspondence
    Panos Roussos, M.D., Ph.D.
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York

    Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, New York
    Search for articles by this author
  • Author Footnotes
    1 GEH and YM contributed equally to this work.

      Abstract

      Background

      While schizophrenia differs between males and females in the age of onset, symptomatology, and disease course, the molecular mechanisms underlying these differences remain uncharacterized.

      Methods

      To address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA sequencing data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium.

      Results

      Analysis across the cohorts identified a reproducible gene expression signature of schizophrenia that was highly concordant with previous work. Differential expression across sex was reproducible across cohorts and identified X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature was also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality from thousands of genes to dozens of modules and elucidate interactions among genes. We found enrichment of coexpression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involved a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation.

      Conclusions

      Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

      Keywords

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