Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery

Abstract

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10^-5; ΔAIC = -10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10^-141), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10^-6), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies.

Fig. 1

a Heatmap of pairwise TOM scores, aligned with the relevant dendrogram branches, of genes assigned to the seven baseline modules. b Correlation heatmap and dendrogram of eigengene profiles for baseline modules (including SZ status). c Two-dimensional network of gene-gene connection strengths (adjacency matrix values; minimum of 0.01) created in Cytoscape v. 3.6.0. Node colors correspond to baseline modules to which the genes were assigned. Top results from gene enrichment analyses of GO-terms and KEGG pathways are also shown, with Fisher’s Exact P-values in parentheses

Fig. 2

a Heatmap of pairwise TOM scores, aligned with the relevant dendrogram branches, of genes assigned to the six DA-stimulated modules. b Correlation heatmap and dendrogram of eigengene profiles for DA-stimulated modules (including SZ status). c Two-dimensional network of gene-gene connection strengths (adjacency matrix values; minimum of 0.01) created in Cytoscape v. 3.6.0. Node colors correspond to DA-stimulated modules to which the genes were assigned. Top results from gene enrichment analyses of GO-terms and KEGG pathways are also shown, with Fisher’s Exact P-values in parentheses