Patients with schizophrenia and bipolar disorder display a similar global gene expression signature in whole blood that reflects elevated proportion of immature neutrophil cells with association to lipid changes

Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) share clinical characteristics, genetic susceptibility, and immune alterations. We aimed to identify differential transcriptional patterns in peripheral blood cells of patients with SCZ or BD versus healthy controls (HC). We analyzed microarray-based global gene expression data in whole blood from a cohort of SCZ (N = 329), BD (N = 203) and HC (N = 189). In total, 65 genes were significantly differentially expressed in SCZ and 125 in BD, as compared to HC, with similar ratio of up- and downregulated genes in both disorders. Among the top differentially expressed genes, we found an innate immunity signature that was shared between SCZ and BD, consisting of a cluster of upregulated genes (e.g., OLFM4, ELANE, BPI and MPO) that indicate an increased fraction of immature neutrophils. Several of these genes displayed sex differences in the expression pattern, and post-hoc analysis demonstrated a positive correlation with triglyceride and a negative correlation with HDL cholesterol. We found that many of the downregulated genes in SCZ and BD were associated with smoking. These findings of neutrophil granulocyte-associated transcriptome signatures in both SCZ and BD point at altered innate immunity pathways with association to lipid changes and potential for clinical translation.

Fig. 1. Volcano plot of the differentially expressed genes.

A Schizophrenia vs healthy controls. B Bipolar disorder vs healthy controls. NS = not significant.

Fig. 2. Co-expression matrix of top 10 differentially expressed genes (up- and downregulated) and selected blood markers.

A Schizophrenia and (B) Bipolar disorder. Upregulated genes are written in red, downregulated genes in blue, serum proteins in green, and serum lipids in black. Corresponding to the strength of Pearson correlation, a positive co-expression is indicated in a gradient of blue and a negative co-expression is indicated in a gradient of red. Genes are annotated with their gene symbol. Serum protein annotation: BD1 beta defensin 1, BD2 beta defensin 2, CRP C-reactive protein, HNP13 human neutrophil peptide 1 and 3, MPOprot MPO protein (to differentiate it from the gene with the same name). Significance level is indicated with *p-value < 0.05, **p-value < 0.01 and ***p-value =≤ 0.001.