Differentially expressed mRNAs of neural signaling pathway genes in peripheral blood leukocytes as biomarkers for schizophrenia

Abnormal neurotransmitter regulation plays a role in the pathogenesis of Schizophrenia (SCZ), and the presence of brain tissue-like aberrant expression in the partial transcriptome of peripheral blood leukocytes from patients with SCZ suggests that these aberrantly expressed genes could be potential diagnostic markers. We designed a case-control study to analyze the association between the expression levels of mRNAs and SCZ in peripheral blood leukocytes and to explore their potential value as diagnostic biomarkers for SCZ. Differentially expressed mRNAs associated with neural signaling pathways were screened by RNA sequencing in a small set, comprising 9 patients with SCZ and 20 controls. A case-control study that included 217 cases and 217 controls was further conducted to verify these mRNAs. The differential expression analysis between cases and controls was performed, followed by restricted cubic spline regression analysis. Gene expression score (GES) was constructed for differentially expressed genes to assess their diagnostic value as biomarkers. In SCZ patients, there were higher expression levels of CREB5, PPP3R1 and PPP1CB (P < 0.05) than in controls. Furthermore, DUSP1 and MAPK13 downregulated in undifferentiated SCZ and acute schizophrenia-like psychotic disorder (P < 0.05), PPP3R1 expression upregulated in paranoid SCZ, undifferentiated SCZ and acute schizophrenia-like psychotic disorder (P < 0.01), and CREB5 exclusively upregulated in paranoid SCZ (P = 0.001), respectively. The risk of SCZ was nonlinearly correlated with DUSP1, GNG10, GNG7, PRKACA, CREB5, PPP3R1 and PPP1CB (P_overall < 0.05, P_nonlinear < 0.05). Meanwhile, incorporating these 7 genes into the GES improved the model's area under curve to 0.743, significantly enhancing the diagnostic discriminatory ability for SCZ.