Proceedings of The Physiological Society
King's College London (2011) Proc Physiol Soc 22, C20
Elucidating the functions of the schizophrenia susceptibility gene ZNF804A using human neural cells
M. Hill1, N. Bray1
1. Neuroscience, Institute of Psychiatry, KCL, London, United Kingdom.
Genome-wide association studies have identified susceptibility genes for common psychiatric disorders with unprecedented confidence. The first genome-wide significant finding for the broad phenotype of psychosis (encompassing both schizophrenia and bipolar disorder) was with a variant within the ZNF804A gene (O'Donovan et al, 2008). Although the associated gene variant appears to impact on brain structure and activity (Esslinger et al, 2009), ZNF804A has, to date, been a gene of unknown function. In order to shed light on the functions of ZNF804A in an unbiased manner, we manipulated its expression in human neural progenitor cells using RNA interference and assessed effects on the cellular transcriptome using whole genome microarrays. Transcriptional consequences of the two non-overlapping siRNA targetting ZNF804A were compared with a control siRNA (n=4 for each of the 3 conditions). There were 153 nominally significant (t-test P < 0.05) probe expression differences between ZNF804A siRNA and control conditions that were shared by the two ZNF804A siRNA conditions. Gene ontology analysis using DAVID bioinformatics resources (http://david.abcc.ncifcrf.gov) showed a significant (P = 0.002) enrichment of genes involved in 'biological adhesion'. We sought to confirm the most significant gene expression changes shared by the two ZNF804A siRNA conditions in repeat experiments using qPCR. Two of the 3 genes showing consistent gene expression changes across experiments are involved in neurite outgrowth; the other is of unknown function. These data demonstrate how transcriptional profiling in appropriate cell systems can be used to generate hypotheses as to the physiological role of genes of unknown function.
Where applicable, experiments conform with Society ethical requirements