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Genetic identification of brain cell types underlying schizophrenia

Skene, Nathan G., Bryois, Julien, Bakken, Trygve E., Breen, Gerome, Crowley, James J., Gaspar, Héléna A., Giusti-Rodriguez, Paola, Hodge, Rebecca D., Jeremy A., Miller, Muñoz-Manchado, Ana, O'Donovan, Michael C. ORCID:, Owen, Michael J. ORCID:, Pardinas, Antonio ORCID:, Ryge, Jesper, Walters, James T. R. ORCID:, Linnarsson, Sten, Lein, Ed S., Sullivan, Patrick F. and Hjerling-Leffler, Jens 2018. Genetic identification of brain cell types underlying schizophrenia. Nature Genetics 50 , pp. 825-833. 10.1038/s41588-018-0129-5

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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. 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, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to sets of genes specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (synaptic genes, FMRP interactors, antipsychotic targets, etc.) generally implicate 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 medium spiny neurons did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Publisher: Nature
ISSN: 1061-4036
Date of First Compliant Deposit: 1 February 2018
Date of Acceptance: 3 April 2018
Last Modified: 07 Nov 2023 00:10

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