Abstract
Background The ganglionic eminences are fetal-specific structures that give rise to gamma- aminobutyric acid (GABA)- and acetylcholine- releasing neurons of the forebrain. Given evidence for GABAergic and cholinergic disturbances in schizophrenia, as well as an early neurodevelopmental component to the disorder, we tested the potential involvement of developing cells of the ganglionic eminences 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 ganglionic eminences to test enrichment of schizophrenia risk variation in genes with high expression specificity for particular developing cell populations within these structures. 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 ganglionic eminences, using these to additionally 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 also concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the ganglionic eminences.
Conclusions Our study provides evidence for a role of prenatal GABAergic and cholinergic neuron development in later susceptibility to schizophrenia.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This work was supported by a Medical Research Council (UK) project grant (MR/T002379/1) and funding for the Psychiatric Genomics Consortium through National Institute of Mental Health (USA) award R01MH124873.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The London - Fulham Research Ethics Committee and North East - Newcastle & North Tyneside 1 Research Ethics Committee granted the Human Developmental Biology Resource ethical approval to collect and distribute fetal tissue for research, stating that this approval applies to all research projects conducted in the UK using tissue or data supplied by the tissue bank.
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Data availability
Gene expression cell specificity values and the genomic coordinates of all open chromatin regions identified in this study are provided in Supplementary Tables.