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

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, Joel E. Kleinman, Daniel R. Weinberger, Apuã C. M. Paquola () and Jennifer A. Erwin ()
Additional contact information
Kynon J. M. Benjamin: Lieber Institute for Brain Development
Ria Arora: Lieber Institute for Brain Development
Arthur S. Feltrin: Lieber Institute for Brain Development
Geo Pertea: Lieber Institute for Brain Development
Hunter H. Giles: Lieber Institute for Brain Development
Joshua M. Stolz: Lieber Institute for Brain Development
Laura D’Ignazio: Lieber Institute for Brain Development
Leonardo Collado-Torres: Lieber Institute for Brain Development
Joo Heon Shin: Lieber Institute for Brain Development
William S. Ulrich: Lieber Institute for Brain Development
Thomas M. Hyde: Lieber Institute for Brain Development
Joel E. Kleinman: Lieber Institute for Brain Development
Daniel R. Weinberger: Lieber Institute for Brain Development
Apuã C. M. Paquola: Lieber Institute for Brain Development
Jennifer A. Erwin: Lieber Institute for Brain Development

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48048-z

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