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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1450664

Reported race-associated differences in control and schizophrenia post-mortem brain transcriptomes implicate stress-related and neuroimmune pathways

Provisionally accepted
Shay Simmons Shay Simmons 1,2*Keon Arbabi Keon Arbabi 1,2*Daniel Felsky Daniel Felsky 1,2,3,4Michael Wainberg Michael Wainberg 2,5*Shreejoy Tripathy Shreejoy Tripathy 1,2,3,6*
  • 1 Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 2 Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  • 3 Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 4 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  • 5 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  • 6 Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

The final, formatted version of the article will be published soon.

    The molecular mechanisms underlying racial disparities in schizophrenia (SCZ) illness courses and outcomes are poorly understood. While these differences are thought to arise partly through stressful social gradients, little is known about how these differences are reflected in the brain, nor how they might underlie disparate psychiatric outcomes. To better understand the neuro-molecular correlates of social gradients, SCZ, and their overlap, we analyzed post-mortem dorsolateral prefrontal cortex (DLPFC) RNAseq data from two racially diverse cohorts in the CommonMind Consortium (235 reported Black and 546 White; 322 SCZ cases and 459 controls) using differential expression and gene set variation analyses. We observed differences in brain gene expression that were consistent across cohorts and reported race. A combined mega-analysis identified 1514 genes with differential expression (DE) between reported races after accounting for diagnosis and other covariates. Functional enrichment analyses identified upregulation of genes involved in stress and immune response, highlighting the potential role of environmental differences between reported race groups. In a race-by-diagnosis interaction analysis, no individual genes passed statistical significance. However, 109 gene sets showed statistically significant differences, implicating metabolic and immune pathways. Our results suggest molecular mechanisms uniquely perturbed across reported race groups and identify several candidate pathways associated with SCZ in a reported race-dependent manner. Our results underscore the importance of diverse cohort ascertainment to better capture population-level differences in SCZ pathogenesis.

    Keywords: Simmons 2 Computational Psychiatry, Neuroscience, Health Disparities, Transcriptomics, Gene Expression, population health, Health Outcomes, Social genomics

    Received: 17 Jun 2024; Accepted: 17 Sep 2024.

    Copyright: © 2024 Simmons, Arbabi, Felsky, Wainberg and Tripathy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Shay Simmons, Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, Ontario, Canada
    Keon Arbabi, Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, M6J 1H4, Ontario, Canada
    Michael Wainberg, Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, M6J 1H4, Ontario, Canada
    Shreejoy Tripathy, Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, M6J 1H4, Ontario, Canada

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