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Single nuclei RNA sequencing of 5 regions of the human prenatal brain implicates developing neuron populations in genetic risk for schizophrenia

Cameron, Darren, Mi, Da, Vinh, Ngoc-Nga, Webber, Caleb ORCID: https://orcid.org/0000-0001-8063-7674, Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643, Marin, Oscar, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379 and Bray, Nicholas ORCID: https://orcid.org/0000-0002-4357-574X 2022. Single nuclei RNA sequencing of 5 regions of the human prenatal brain implicates developing neuron populations in genetic risk for schizophrenia. Biological Psychiatry 10.1016/j.biopsych.2022.06.033

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Abstract

Background While a variety of evidence supports a prenatal component to schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single nuclei RNA sequencing with recent large-scale GWAS and exome sequencing data for the condition. Methods Single nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population. Results Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability. Conclusions We find evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neuron within the second trimester fetal brain. Our study significantly advances understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurological disorders.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Creative Commons Attribution (CC BY 4.0)
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 12 July 2022
Date of Acceptance: 29 June 2022
Last Modified: 10 Nov 2022 23:40
URI: https://orca.cardiff.ac.uk/id/eprint/151244

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