School of Medicine Publications and Presentations
Document Type
Article
Publication Date
8-2018
Abstract
The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.
Recommended Citation
Duan, J., Göring, H.H.H., Sanders, A.R. et al. Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model. Transl Psychiatry 8, 158 (2018). https://doi.org/10.1038/s41398-018-0216-5
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Translational Psychiatry
DOI
10.1038/s41398-018-0216-5
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© The Author(s) 2018. Original published version available at https://dx.doi.org/10.1038%2Fs41398-018-0216-5