Genetic implication of specific glutamatergic neurons of the prefrontal cortex in the pathophysiology of schizophrenia

Tume, Claire E., Chick, Sophie L., Holmans, Peter A. ORCID: https://orcid.org/0000-0003-0870-9412, Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Cameron, Darren and Bray, Nicholas J. ORCID: https://orcid.org/0000-0002-4357-574X 2024. Genetic implication of specific glutamatergic neurons of the prefrontal cortex in the pathophysiology of schizophrenia. Biological Psychiatry 4 (5) , 100345. 10.1016/j.bpsgos.2024.100345

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Abstract

Background: The prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. We here combine high-resolution single nuclei RNA sequencing (snRNA-Seq) data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder. Methods: Gene expression specificity values were calculated from a snRNA-Seq dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood. Enrichment of schizophrenia common variant liability and burden of rare protein-truncating coding variants was tested in genes with high expression specificity for each cell type. We additionally explored schizophrenia common variant associations in relation to gene expression across the developmental trajectory of implicated neurons. Results: Common risk variation for schizophrenia was prominently enriched in genes with high expression specificity for a population of mature layer 4 glutamatergic neurons emerging in infancy. Common variant liability to schizophrenia increased along the developmental trajectory of this neuronal population. Fine-mapped genes at schizophrenia GWAS risk loci had significantly higher expression specificity than other genes in these neurons and in a population of layer 5/6 glutamatergic neurons. People with schizophrenia had a higher rate of rare protein-truncating coding variants in genes expressed by cells of the PFC than control individuals, but no cell population was significantly enriched above this background rate. Conclusions: We identify a population of layer 4 glutamatergic PFC neurons likely to be particularly impacted by common variant genetic risk for schizophrenia, which may contribute to disturbances in thalamocortical connectivity in the condition.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences
Publisher:	Elsevier
ISSN:	1873-2402
Funders:	MRC, UKRI
Date of First Compliant Deposit:	7 June 2024
Date of Acceptance:	19 May 2024
Last Modified:	03 Sep 2024 13:00
URI:	https://orca.cardiff.ac.uk/id/eprint/169578

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