Genetic identification of brain cell types underlying schizophrenia
File(s)Resubmission NG-A46291_.pdf (1.56 MB)
Accepted version
OA Location
Author(s)
Type
Journal Article
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.
Date Issued
2018-06-01
Date Acceptance
2018-04-03
Citation
Nature Genetics, 2018, 50 (6), pp.825-833
ISSN
1061-4036
Publisher
Nature Research
Start Page
825
End Page
833
Journal / Book Title
Nature Genetics
Volume
50
Issue
6
Copyright Statement
© 2018 Nature America Inc., part of Springer Nature. All rights reserved. The final publication is available at Springer via [insert hyperlinked DOI]
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000433621000010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
NUCLEUS RNA-SEQ
NEURONAL SUBTYPES
DISEASE
LOCI
MOUSE
RISK
METAANALYSIS
INDIVIDUALS
DIVERSITY
Publication Status
Published
Date Publish Online
2018-05-21