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.
| Original language | English (US) |
|---|---|
| Article number | 3980 |
| Journal | Nature communications |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
The authors would like to extend their appreciation to the Offices of the Chief Medical Examiner of Washington DC, Northern Virginia, Kalamazoo Michigan, Santa Clara County, University of North Dakota, and Maryland for the provision of brain tissue used in this work. The authors also extend their posthumus appreciation to Dr. Llewellyn B. Bigelow and members of the LIBD Neuropathology Section for their work in assembling and curating the clinical and demographic information and organizing the Human Brain Tissue Repository of the Lieber Institute. Finally, the authors gratefully acknowledge the families that have donated this tissue to advance our understanding of psychiatric disorders. We also thank Karen Ives for her editorial support. This work is supported by the Lieber Institute for Brain Development, the National Institutes of Health (NIH) T32 fellowship (T32MH015330) and K99 award (K99MD016964) to K.J.M.B., NIH R01 (R01MH123183) to L.C.-T., and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to J.A.E. R.A. would like to thank the Hopkins Office for Undergraduate Research (HOUR), Johns Hopkins University for their support through the Summer PURA program as well as the Albstein Research Scholarship for their support. This research was supported by the Intramural Research Program of the NIMH (NCT00001260, 900142).
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy