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Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function

Flynn, Mairéad
; 
Whitton, Laura
; 
Donohoe, Gary
; 
Morrison, Ciaran G.
; 
Morris, Derek W.

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http://hdl.handle.net/10379/16274
 https://doi.org/10.13025/15406

Date

2019-12-23

Keywords

susceptibility loci , cell-migration , primary cilia , metaanalysis , centrosome , risk , disease , association , recruitment , hedgehog

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journal article

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Citation

Flynn, Mairéad, Whitton, Laura, Donohoe, Gary, Morrison, Ciaran G, & Morris, Derek W. (2019). Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function. Human Molecular Genetics, 29(3), 407-417. doi:10.1093/hmg/ddz292

Abstract

Mutations in genes that encode centrosomal/ciliary proteins cause severe cognitive deficits, while common single-nucleotide polymorphisms in these genes are associated with schizophrenia (SZ) and cognition in genome-wide association studies. The role of these genes in neuropsychiatric disorders is unknown. The ciliopathy gene SDCCAG8 is associated with SZ and educational attainment (EA). Genome editing of SDCCAG8 caused defects in primary ciliogenesis and cilium-dependent cell signalling. Transcriptomic analysis of SDCCAG8-deficient cells identified differentially expressed genes that are enriched in neurodevelopmental processes such as generation of neurons and synapse organization. These processes are enriched for genes associated with SZ, human intelligence (IQ) and EA. Phenotypic analysis of SDCCAG8-deficent neuronal cells revealed impaired migration and neuronal differentiation. These data implicate ciliary signalling in the aetiology of SZ and cognitive dysfunction. We found that centrosomal/ciliary genes are enriched for association with IQ, suggesting altered gene regulation as a general model for neurodevelopmental impacts of centrosomal/ciliary genes.

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College of Science, National University of Ireland, Galway
Irish Research Council
Thomas Crawford Hayes Trust Research Fellowship

Publisher

Oxford University Press (OUP)

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License

CC BY-NC-ND

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