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Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

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  • Kynon J. M. Benjamin

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Ria Arora

    (Lieber Institute for Brain Development
    Johns Hopkins University Krieger School of Arts & Sciences)

  • Arthur S. Feltrin

    (Lieber Institute for Brain Development)

  • Geo Pertea

    (Lieber Institute for Brain Development)

  • Hunter H. Giles

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine)

  • Joshua M. Stolz

    (Lieber Institute for Brain Development)

  • Laura D’Ignazio

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine)

  • Leonardo Collado-Torres

    (Lieber Institute for Brain Development
    Johns Hopkins University)

  • Joo Heon Shin

    (Lieber Institute for Brain Development)

  • William S. Ulrich

    (Lieber Institute for Brain Development)

  • Thomas M. Hyde

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Joel E. Kleinman

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine)

  • Daniel R. Weinberger

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Apuã C. M. Paquola

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine)

  • Jennifer A. Erwin

    (Lieber Institute for Brain Development
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

Suggested Citation

  • Kynon J. M. Benjamin & Ria Arora & Arthur S. Feltrin & Geo Pertea & Hunter H. Giles & Joshua M. Stolz & Laura D’Ignazio & Leonardo Collado-Torres & Joo Heon Shin & William S. Ulrich & Thomas M. Hyde &, 2024. "Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48048-z
    DOI: 10.1038/s41467-024-48048-z
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