The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
Genetic identification of brain cell types underlying schizophrenia
Open accessPublished version of a preprint
Abstract
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.
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“The atlas will also help us understand the function of specific genes—for example, those implicated in disease (Skene et al., 2018).”
From Molecular Architecture of the Mouse Nervous System (2018) · cites this paper as Skene et al., 2018
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“A similar result was observed using a mouse single-cell dataset14”
From New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) · cites this paper as [14]
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“In mouse single-cell RNA-seq data16, we found similar patterns of enrichments in genes with high expression in excitatory glutamatergic pyramidal neurons from the cortex and hippocampus (Figure 4b), and inhibitory cortical interneurons.”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [16]
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“Briefly, brain-cell-type expression data were drawn from single-cell RNA-seq data from mouse brains.”
From Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence (2018) · cites this paper as [53]
In the citing paper
“We also identified a significant gene-set (P = 3.87 × 10-5) containing somatosensory pyramidal neurons using brain cell-type data from Skene, et al. 15 (Table 3).”
From Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions (2019) · cites this paper as [15]
In the citing paper
“Common variation in SCZ maps onto specific groups of cells including pyramidal neurons and medium spiny neurons31.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [31]
In the citing paper
“At present, many psychiatric GWAS are under-powered to accomplish these intentions (Skene et al., 2018).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Skene et al., 2018
In the citing paper
“This inhibitory neuron-related module is not enriched for common or rare genetic disease-associated variation, although other studies have found enrichment for SCZ GWAS signal among interneuron markers defined in other ways (63).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [63]
In the citing paper
“Here, we found widespread enrichments across central nervous system neurons with limited to no signal in glial cells and peripheral nervous system neurons (Table S10, Figure S17).”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [33]
In the citing paper
“In contrast to AD in which multiple glial cells are implicated, previous work has indicated neurons as the central cell-type harboring genetic risk for the majority of psychiatric disorders3,22,46,58–61.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [61]
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Citations
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Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
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Self-citationMAGMA: Generalized Gene-Set Analysis of GWAS Data
de Leeuw, C. A., Mooij, J. M., Heskes, T., & Posthuma, D. (2015) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1004219 · Cited by 3,653
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Zeisel, A., Muñoz-Manchado, A. B., Codeluppi, S., Lönnerberg, P., La Manno, G., Juréus, A., Marques, S., Munguba, H., He, L., Betsholtz, C., et al. (2015) · Science · doi:10.1126/science.aaa1934 · Cited by 3,124
Self-citationA subcellular map of the human proteome
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USING THE CORRECT STATISTICAL TEST FOR THE EQUALITY OF REGRESSION COEFFICIENTS
Paternoster, R., Brame, R. W., Mazerolle, P., & Piquero, A. R. (1998) · Criminology · doi:10.1111/j.1745-9125.1998.tb01268.x · Cited by 2,755
Partitioning heritability by functional annotation using genome-wide association summary statistics
ReproGen Consortium, Finucane, H. K., Schizophrenia Working Group of the Psychiatric Genomics Consortium, The RACI Consortium, Bulik-Sullivan, B., Gusev, A., Trynka, G., Reshef, Y., Loh, P.-R., Anttila, V., et al. (2015) · Nature Genetics · doi:10.1038/ng.3404 · Cited by 2,604
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Self-citationMolecular Architecture of the Mouse Nervous System
Zeisel, A., Hochgerner, H., Lönnerberg, P., Johnsson, A., Memic, F., van der Zwan, J., Häring, M., Braun, E., Borm, L. E., La Manno, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.021 · Cited by 2,552
Self-citationMapping genomic loci implicates genes and synaptic biology in schizophrenia
Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C.-Y., Dennison, C. A., Hall, L. S., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964
Self-citationNew insights into the genetic etiology of Alzheimer’s disease and related dementias
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Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0326-7 · Cited by 2,565
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Metadata
- Authors
- Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Skene, N. G., Bryois, J., Bakken, T. E., Breen, G., Crowley, J. J., Gaspar, H. A., Giusti-Rodriguez, P., Hodge, R. D., Miller, J. A., Muñoz-Manchado, A. B., O’Donovan, M. C., Owen, M. J., Pardiñas, A. F., Ryge, J., Walters, J. T. R., Linnarsson, S., Lein, E. S., Sullivan, P. F., & Hjerling-Leffler, J.
- Affiliations
- Karolinska Institutet (SE)
- Allen Institute for Brain Science (US)
- National Health Service (GB)
- University of North Carolina at Chapel Hill (US)
- Cardiff University (GB)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Sullivan, Patrick F.
- ORCID
- Skene, Nathan G.
- Bryois, Julien
- Bakken, Trygve E.
- Breen, Gerome
- Crowley, James J.
- Gaspar, Héléna A.
- Giusti-Rodriguez, Paola
- Hodge, Rebecca D.
- Miller, Jeremy A.
- O’Donovan, Michael C.
- Owen, Michael J.
- Pardiñas, Antonio F.
- Ryge, Jesper
- Walters, James T. R.
- Linnarsson, Sten
- Lein, Ed S.
- Sullivan, Patrick F.
- Hjerling-Leffler, Jens
- Venue
- Nature Genetics
- Published
- 2018-05-21
- Volume
- 50
- Issue
- 6
- Pages
- 825-833
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6477180
- OpenAlex
- W2952673268
- Cited by
- 651
- References
- 68
- Citations by year
- 2026: 65 · 2025: 78 · 2024: 75 · 2023: 70 · 2022: 93 · 2021: 74 · 2020: 88 · 2019: 68 · 2018: 36
- FWCI
- 52.16
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- RODIN (Universidad de Cádiz) (submittedVersion, cc-by-nc-nd)
- Spiral (Imperial College London) (submittedVersion)
- UNC Libraries
- Funders
- National Science Foundation
- Wellcome Trust (108726, /Z/15/Z, 108726/Z/15/Z)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Hjärnfonden
- Vetenskapsrådet (U01-MH-109528, 2014-03863, D0886501)
- Medical Research Council (MR/L011794/1, MR/P005748/1, MR/L010305/1)
- National Institute of Mental Health (U01MH109514, U01MH109528, U01MH109536, MH109532, MH109528, U01MH109532)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- schizophrenia, brain cell types, single-cell RNA sequencing, genome-wide association study, common genetic variants, medium spiny neurons, interneurons, FMRP, synaptic function, genetic risk
- MeSH terms
- Animals, Brain, Humans, Neurons, Schizophrenia, Genetic Predisposition to Disease, Genomics, Mice, Genome-Wide Association Study
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