Transcriptional changes following cellular knockdown of the schizophrenia risk gene SETD1A are enriched for common variant association with the disorder

Cameron, Darren, Blake, Derek J. ORCID: https://orcid.org/0000-0002-5005-4731, Bray, Nicholas J. ORCID: https://orcid.org/0000-0002-4357-574X and Hill, Matthew J. ORCID: https://orcid.org/0000-0001-6776-8709 2019. Transcriptional changes following cellular knockdown of the schizophrenia risk gene SETD1A are enriched for common variant association with the disorder. Molecular Neuropsychiatry 5 (2) , pp. 109-114. 10.1159/000497181

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Abstract

Loss of function mutations in SETD1A are the first experiment-wide significant findings to emerge from exome sequencing studies of schizophrenia. Although SETD1A 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 of SETD1A could confer risk for schizophrenia, we have performed genome-wide gene expression profiling of a commonly used human neuroblastoma cell line in which SETD1A 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 as DCX and DLX5. 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Publisher:	Karger Publishers
ISSN:	2296-9209
Date of First Compliant Deposit:	30 January 2019
Date of Acceptance:	22 January 2019
Last Modified:	26 Jul 2024 16:26
URI:	https://orca.cardiff.ac.uk/id/eprint/119028

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