Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. To date, only the prefrontal cortex has been examined in large-scale transcriptome analyses for sex differences in schizophrenia. Here, we examined the BrainSeq Consortium RNA-sequencing and genotypes for the caudate nucleus (n=399), dorsolateral prefrontal cortex (DLPFC; n=377), and hippocampus (n=394) to characterize sex differences in schizophrenia. We identified genomic features (genes, transcripts, exons, and exon-exon junctions) associated with sex, sex-specific expression in schizophrenia, and sex-interacting expression quantitative trait loci (si-eQTL) associated with schizophrenia risk. We found 878 unique genes with sex differences across brain regions, including ANK3, which shows male-biased expression in the caudate nucleus. X-chromosome dosage was significantly decreased in the hippocampus of female and male individuals with schizophrenia. Our sex interaction model revealed 15 novel junctions dysregulated for schizophrenia in a sex-specific manner. Sex-specific schizophrenia analysis identified dozens of expressed, sex-specific features with enrichment in the transcriptional response of cellular stress. Finally, our si-eQTL analysis revealed 974 unique genes, 14 of which are associated with schizophrenia risk. Overall, our results increased the number of annotated sex-biased features, identified sex-specific schizophrenia genes, and provided the first annotation of si-eQTL in the human DLPFC and hippocampus. Altogether, these results point to the importance of sex-informed analysis of sexually dimorphic traits and inform personalized therapeutic strategies in schizophrenia.

The authors have declared no competing interest.

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 KJMB, NIH R01 (R01MH123183) to LC-T, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to JAE.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The research described herein complies with all relevant ethical regulations. All specimens used in this study were obtained with informed consent from the next kin under protocols No. 12-24 from the Department of Health and Mental Hygiene for the Office of the Chief Medical Examiner for the State of Maryland, and No. 20111080 for the Western Institutional Review Board for the Offices of the Chief Medical Examiner for Kalamazoo Michigan, University of North Dakota in Grand Forks North Dakota, and Santa Clara County California. Details of case selection, curation, diagnosis, and anatomical localization and dissection can be found in previous publications from our research group and are publicly available.

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Publicly available BrainSeq Consortium total RNA DLPFC and hippocampus RangedSummarizedExperiment R Objects with processed counts are available at http://eqtl.brainseq.org/phase2/. Publicly available BrainSeq Consortium total RNA caudate nucleus RangedSummarizedExperiment R Objects with processed counts are available at http://erwinpaquolalab.libd.org/caudate_eqtl/. Analysis-ready genotype data will be shared with researchers that obtain dbGaP access. FASTQ files are available for total RNA DLPFC and hippocampus via Globus collections jhpce#bsp2-dlpfc and jhpce#bsp2-hippo. For the caudate nucleus, FASTQ files are available on NCBI SRA under project ID PRJNA874683. PGC3 GWAS summary statistics are available at https://figshare.com/articles/dataset/scz2022/19426775.

https://doi.org/10.5281/zenodo.7125280