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.
Highlights
Schizophrenia (SZ) is a disabling mental disorder characterized by severe disturbances in thought, behavior, and emotion, including psychotic symptoms and cognitive impairment[1]
The subjects are of European ancestry and represent a subset of the Molecular Genetics of Schizophrenia (MGS) collection selected for genomewide association studies (GWAS) and analyses of CNVs and transcriptomics[16,17,18,19,20]
At 100 μM, significant changes were observed for gene expression throughout the genome, affecting approximately 13% of genes, with only limited effects on lymphoblastoid cell lines (LCLs) growth, and 100 μM was selected for DA perturbation of the larger study sample
Summary
Schizophrenia (SZ) is a disabling mental disorder characterized by severe disturbances in thought, behavior, and emotion, including psychotic symptoms and cognitive impairment[1]. Kos et al Translational Psychiatry (2018)8:278 longstanding SZ model, attributing positive symptoms of the disorder, in particular psychosis, to dysregulation in dopaminergic neurotransmission via the dopamine (DA) receptor D2 (DRD2). This is supported by effects of psychotogenic stimulants (e.g., amphetamines) that activate DA receptors, as in vivo brain imaging studies have shown that amphetamine-induced increases in DA response are correlated with positive symptoms of SZ4,5. Metaanalysis of brain imaging data have shown increased postsynaptic DRD2 density in the striatum of SZ patients, but the relationship is complicated by the absence of significant differences between drug-naïve patients and controls, suggesting that the DRD2 upregulation may be due to antipsychotic treatment[7]. Results from genomewide association studies (GWAS) do show an association between common variants at the DRD2 locus and SZ8, supporting the contention that D2 receptor variants affect SZ risk
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.