Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia

Cameron, Darren, Vihn, Ngoc-Nga, Prapaiwongs, Parinda, Perry, Elizabeth A., Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379 and Bray, Nicholas ORCID: https://orcid.org/0000-0002-4357-574X 2024. Genetic implication of prenatal GABAergic and cholinergic neuron development in susceptibility to schizophrenia. Schizophrenia Bulletin Open 10.1093/schbul/sbae083

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Abstract

Background The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition. Study Design We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder. Study Results Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE. Conclusions Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	2632-7899
Date of First Compliant Deposit:	7 June 2024
Date of Acceptance:	13 May 2024
Last Modified:	17 Jun 2024 13:25
URI:	https://orca.cardiff.ac.uk/id/eprint/169583

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