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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:, Rees, Elliott ORCID:, O'Donovan, Michael C. ORCID:, Cameron, Darren and Bray, Nicholas J. ORCID: 2024. Genetic implication of specific glutamatergic neurons of the prefrontal cortex in the pathophysiology of schizophrenia. Biological Psychiatry 10.1016/j.bpsgos.2024.100345
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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: Published Online
Status: In Press
Schools: Medicine
ISSN: 1873-2402
Date of First Compliant Deposit: 7 June 2024
Date of Acceptance: 19 May 2024
Last Modified: 13 Jul 2024 21:45

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