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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??M). 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; ?AIC?=?-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.


PROVIDER: S-EPMC6293320 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

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