Sex and regional differences in gene expression across the striatum in psychosis

Psychosis is a hallmark symptom of schizophrenia and highly prevalent in bipolar disorder. Previous work has shown altered gene expression within subregions of the striatum in subjects with psychosis, but it is unclear if these alterations differ across subregions. Moreover, despite known sex differences in the presentation of psychosis (such as age of onset and disease course), it is unclear if there are sex differences in gene expression across subregions of the human striatum in the context of psychosis. Using RNA-sequencing data from human postmortem nucleus accumbens (NAc), caudate, and putamen, we first performed differential expression analyses across these striatal subregions in unaffected (n = 60) and psychosis (n = 36) subjects. For analysis of sex differences, we used equal numbers of males and females in each subject group and evaluated sex and psychosis effects within each brain region. We found that the NAc is the most transcriptionally unique region compared to the caudate and the putamen in both psychosis and unaffected subjects. We also found distinct patterns in gene expression across the three striatal subregions, with an altered pattern of cilia-related genes in subjects with psychosis. Our sex-based analyses showed a striking discordant expression pattern, with opposite effect directions between male and female subjects with psychosis in all three subregions, including a reversal of sex differences in immune- and angiogenesis-related pathways. Overall, we identified regional and sex differences in gene expression across the human striatum that may underlie sex-specific striatal dysfunction and symptomatology in psychosis.