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Opposite Molecular Signatures of Depression in Men and Women

  • Marianne L. Seney
    Correspondence
    Address correspondence to Marianne L. Seney, Ph.D., University of Pittsburgh, 450 Technology Drive, Bridgeside Point II, Pittsburgh, PA 15219.
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Zhiguang Huo
    Affiliations
    Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Kelly Cahill
    Affiliations
    Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Leon French
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Rachel Puralewski
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Joyce Zhang
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Ryan W. Logan
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Center for Systems Neurogenetics of Addiction, Jackson Laboratory, Bar Harbor, Maine
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  • George Tseng
    Affiliations
    Department of Computational and Systems Biology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • David A. Lewis
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Etienne Sibille
    Correspondence
    Etienne Sibille, Ph.D., CAMH, 250 College St, Toronto, Ontario M5T 1R8, Canada.
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    Neurobiology of Depression and Aging, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
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Published:February 03, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.01.017

      Abstract

      Background

      Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex.

      Methods

      To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type–specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]).

      Results

      Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type–specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types.

      Conclusions

      The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.

      Keywords

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      Linked Article

      • Sex-Specific Molecular Changes in Depression
        Biological PsychiatryVol. 84Issue 1
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          Transcriptional profiling of postmortem brain tissue provides detailed insight into the molecular and cellular basis of psychiatric illnesses that cannot be achieved in living patients. A recent large-scale analysis of cortical gene transcriptome profiles across five major psychiatric diseases revealed pathways of molecular convergence and specificity (1). Interestingly, bipolar disorder had more transcriptional overlap with schizophrenia than major depressive disorder (MDD). Furthermore, while autism spectrum disorder showed some genetic overlap with schizophrenia and bipolar disorder, it showed its own module-level differential expression of microglial genes.
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