Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene < b > < i > SETD1A < /i > < /b > Are Enriched for Common Variant Association with the Disorder

Loss of function mutations inSETD1A are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. AlthoughSETD1A is known to encode a histone methyltransferase, the consequences of reduced SETD1A activity on gene expression in neural cells have, to date, been unknown. To explore transcriptional changes through which genetic perturbation ofSETD1A could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in whichSETD1A expression has been experimentally reduced using RNA interference (RNAi). We identified 1,031 gene expression changes that were significant in two separate RNAi conditions compared with control, including effects on genes of known neurodevelopmental importance such asDCX andDLX5. Genes that were differentially expressed following SETD1A knockdown were enriched for annotation to metabolic pathways, peptidase regulator activity and integrin-mediated regulation of cell adhesion. Moreover, differentially expressed genes were enriched for common variant association with schizophrenia, suggesting a degree of molecular convergence between this rare schizophrenia risk factor and susceptibility variants for the disorder operating more generally.Mol Neuropsychiatry

Source: Molecular Neuropsychiatry - March 31, 2019 Category: Neuroscience Source Type: research