Transcriptional and genetic sex differences for schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

This is supplementary data for the manuscript, "Transcriptional and genetic sex differences for schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus".

Abstract: 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 do this by identifying 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 male and female schizophrenic individuals. 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.