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Nat Genet. 2018 Jun;50(6):825-833. doi: 10.1038/s41588-018-0129-5. Epub 2018 May 21.

Genetic identification of brain cell types underlying schizophrenia.

Author information

1
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
2
UCL Institute of Neurology, Queen Square, London, UK.
3
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
4
Allen Institute for Brain Science, Seattle, WA, USA.
5
King's College London, Institute of Psychiatry, Psychology and Neuroscience, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UK.
6
National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, UK.
7
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
8
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
9
Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
10
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. patrick.sullivan@ki.se.
11
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. patrick.sullivan@ki.se.
12
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. jens.hjerling-leffler@ki.se.

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.

PMID:
29785013
PMCID:
PMC6477180
DOI:
10.1038/s41588-018-0129-5
[Indexed for MEDLINE]
Free PMC Article

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