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

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. We thank Uri Frank and Bob Lahue for critical comments on the manuscript. MF received a College of Science Fellowship from NUI Galway, a Government of Ireland Postgraduate Scholarship GOIPG/2016/506 from the Irish Research Council and a Thomas Crawford Hayes Trust Research fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no competing financial interests. peer-reviewed 2020-12-23