M48 - Transcriptomic Signatures of Schizophrenia Revealed By Dopamine Perturbation of Lymphoblastoid Cell Lines

Abstract

Background The dopaminergic hypothesis of schizophrenia postulates a dopamine D2 receptor (DRD2)-mediated hyperdopaminergic neurotransmission in schizophrenia. However, dopamine is also known to have other, non-receptor-mediated effects, including oxidative mechanisms leading to apoptosis. While oxidative processes have been reported to contribute to dopamine neuron loss in Parkinson's disease, their role in schizophrenia remains little studied. Methods We performed a dopamine perturbation on lymphoblastoid cell lines from 515 schizophrenia cases and 692 controls, and studied the resultant RNAseq profiles. Results We found that dopamine had widespread effects on expression profiles, though these effects were likely not mediated through dopamine receptors. Upon stimulation, of the reliably expressed genes, 3,756 (19%) had expression changes of >1 standard deviation at a false discovery rate Discussion Our findings suggest that dopamine may play a role in schizophrenia pathogenesis through modulating immune response and apoptosis. Our results also suggest the utility of pathophysiologically relevant perturbation experiments in appropriate cells to investigate the biology of complex mental disorders.