Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and novel risk genes

Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical controls, 154 patients with schizophrenia, and 44 with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci (eQTLs) analysis, Mendelian Randomization with the latest schizophrenia GWAS, transcriptome wide association study (TWAS), and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We find that antipsychotic medication has an extensive influence on caudate gene expression. We construct caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.