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 studied 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 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. X-chromosome dosage was significantly decreased in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated for schizophrenia in a sex-specific manner. Sex-specific schizophrenia analysis identified dozens of expressed, sex-specific features also with enrichment in immune-related pathways. Finally, our si-eQTL analysis revealed 704 unique genes, nine 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, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.
| S1 | BrainSeq_bySex_genes_3region_eQTL_results.tar.gz | Compressed tar file containing gene eQTL results by sex per brain region including all nominal p-values as well as permutation analysis. |
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| S2 | differential_expression_analysis_4features_sex.txt.gz | Compressed text file of differential expression analysis for sex across the caudate nucleus, DLPFC, and hippocampus for four features (gene, transcript, exon, and exon-exon junction). |
| S3 | BrainSeq_MAGMA_enrichment_results.xlsx | Excel file of magma enrichment results of all DEGs (i.e., sex-specific, sex interacting with brain region, and sex-specific schizophrenia) separated by direction of effect across the caudate nucleus, DLPFC, and hippocampus. |
| S4 | BrainSeq_sex_specific_functional_enrichment_3brain_regions.xlsx | Excel file of GO-term enrichment and GSEA for sex across the caudate nucleus, DLPFC, and hippocampus. |
| S5 | BrainSeq_sex_WGCNA_results.tar.gz | Compressed tar file containing with WGCNA results for autosomal only and all genes sex networks including eigengenes, module membership text files, GO enrichment text and excel file results, and enrichment results with sex DEG analysis for the caudate nucleus, DLPFC, and hippocampus. |
| S6 | BrainSeq_module_preservation_zsummary.xlsx | Excel file of Z summary for module preservation across brain regions for all individuals, control only, and schizophrenia only. |
| S7 | differential_expression_region_interaction_sex_4features.txt | Text file of differential expression analysis for the interaction between brain region and sex for the four features (gene, transcript, exon, and exon-exon junction). |
| S8 | BrainSeq_region_interaction_sex_functional_enrichment.xlsx | Excel file of GSEA for sex and region interaction pairwise enrichment. |
| S9 | BrainSeq_male_biased_genes_XCI_status.tsv | Text file of male-biased (upregulated in male individuals) DEGs across the caudate nucleus, DLPFC, and hippocampus annotated for XCI status. |
| S10 | differential_expression_interaction_jxn.txt | Text file of differentially expressed exon-exon junctions for interaction model of schizophrenia and sex across the caudate nucleus, DLPFC, and hippocampus. |
| S11 | differential_expression_schizophrenia_by_sex_4features.txt.gz | Compressed text file of differential expression analysis for schizophrenia by sex across the caudate nucleus, DLPFC, and hippocampus for four features (gene, transcript, exon, and exon-exon junction). |
| S12 | functional_enrichment_analysis_maleSZ_3brain_regions.txt | Functional enrichment of male-specific schizophrenia across three brain regions using stringent gene list (all DEGs, upregulated and downregulated in schizophrenia). |
| S13 | BrainSeq_sexGenotypes_4features_3regions.txt.gz | Compressed text file of sex-interacting eQTL results across the caudate nucleus, DLPFC, and hippocampus for four features (gene, transcript, exon, and exon-exon junction) generated using mash modeling. |
| S14 | BrainSeq_sex_interacting_eGene_functional_enrichment.xlsx | Excel file of functional enrichment of sex-interacting eQTL associated with unique genes for the caudate nucleus, DLPFC, and hippocampus. |
| S15 | BrainSeq_siEQTL_public_comparison.xlsx | Excel file of si-eQTL shared with the public datasets. |
| S16 | dapg_sex_interacting_eQTL_results.tar.gz | si-eQTL results after fine-mapping across the three brain regions for four features (gene, transcript, exon, and exon-exon junction). |
| S17 | BrainSeq_colocalization_3regions.xlsx | Excel file of gene level colocalization between DAP-G fine-mapped sex-interacting eQTL and schizophrenia GWAS11 on the signal level and individual SNP level using fastENLOC. |