Prefrontal Coexpression of Schizophrenia Risk Genes Is Associated With Treatment Response in Patients

Background: Gene coexpression networks are relevant to functional and clinical translation of schizophrenia risk genes. We hypothesized that schizophrenia risk genes converge into coexpression pathways that may be associated with gene regulation mechanisms and with response to treatment in patients with schizophrenia. Methods: We identified gene coexpression networks in two prefrontal cortex postmortem RNA sequencing datasets (n = 688) and replicated them in four more datasets (n = 1295). We identified and replicated (p values < .001) a single module enriched for schizophrenia risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the schizophrenia risk module via bioinformatic analyses identified two transcription factors and three microRNAs associated with the risk module. To translate postmortem information into clinical phenotypes, we identified polymorphisms predicting coexpression and combined them to obtain an index approximating module coexpression (Polygenic Coexpression Index [PCI]). Results: The PCI-coexpression association was successfully replicated in two independent brain transcriptome datasets (n = 131; p values < .05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with schizophrenia treated with olanzapine (n = 167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (p values < .05). Conclusions: In summary, our findings in 1983 samples of human postmortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This coexpression pathway may be coregulated by transcription factors and microRNA associated with it.