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Genetic identification Of brain cell types underlying schizophrenia

Nathan G. Skene, Julien Bryois, Trygve E. Bakken, Gerome Breen, James J Crowley, Héléna A Gaspar, Paola Giusti-Rodriguez, Rebecca D Hodge, Jeremy A. Miller, Ana Muñoz-Manchado, Michael C O’Donovan, Michael J Owen, Antonio F Pardiñas, Jesper Ryge, James T R Walters, Sten Linnarsson, Ed S. Lein, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, View ORCID ProfilePatrick F Sullivan, Jens Hjerling-Leffler
doi: https://doi.org/10.1101/145466
Nathan G. Skene
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Julien Bryois
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Trygve E. Bakken
Allen Institute for Brain Science, Seattle, Washington 98109, USA
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Gerome Breen
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UKNational Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, UK
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James J Crowley
Departments of Genetics, University of North Carolina, Chapel Hill, NC, 27599–7264, USA
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Héléna A Gaspar
King’s College London, Institute of Psychiatry, Psychology and Neuroscience, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UKNational Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, UK
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Paola Giusti-Rodriguez
Departments of Genetics, University of North Carolina, Chapel Hill, NC, 27599–7264, USA
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Rebecca D Hodge
Allen Institute for Brain Science, Seattle, Washington 98109, USA
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Jeremy A. Miller
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Ana Muñoz-Manchado
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Michael C O’Donovan
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Michael J Owen
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Antonio F Pardiñas
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Jesper Ryge
Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
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James T R Walters
Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
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Sten Linnarsson
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Ed S. Lein
Allen Institute for Brain Science, Seattle, Washington 98109, USA
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Patrick F Sullivan
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, SwedenDepartments of Genetics, University of North Carolina, Chapel Hill, NC, 27599–7264, USA
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  • ORCID record for Patrick F Sullivan
  • For correspondence: mailto:jens.hjerling-leffler@ki.se mailto:patrick.sullivan@ki.se
Jens Hjerling-Leffler
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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  • For correspondence: mailto:jens.hjerling-leffler@ki.se mailto:patrick.sullivan@ki.se
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Abstract

With few exceptions, the marked advances in knowledge about the genetic basis for 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. 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 distinct sets of genes specifically expressed in each of these cell types. Many of the diverse gene sets associated with schizophrenia (including antipsychotic targets) implicate the same brain cell types. Our results provide 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. While some of the genetic risk is associated with GABAergic interneurons, this risk largely does not overlap with that from projecting cells.

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Posted June 02, 2017.
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Genetic identification Of brain cell types underlying schizophrenia
Nathan G. Skene, Julien Bryois, Trygve E. Bakken, Gerome Breen, James J Crowley, Héléna A Gaspar, Paola Giusti-Rodriguez, Rebecca D Hodge, Jeremy A. Miller, Ana Muñoz-Manchado, Michael C O’Donovan, Michael J Owen, Antonio F Pardiñas, Jesper Ryge, James T R Walters, Sten Linnarsson, Ed S. Lein, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Patrick F Sullivan, Jens Hjerling-Leffler
bioRxiv 145466; doi: https://doi.org/10.1101/145466
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Genetic identification Of brain cell types underlying schizophrenia
Nathan G. Skene, Julien Bryois, Trygve E. Bakken, Gerome Breen, James J Crowley, Héléna A Gaspar, Paola Giusti-Rodriguez, Rebecca D Hodge, Jeremy A. Miller, Ana Muñoz-Manchado, Michael C O’Donovan, Michael J Owen, Antonio F Pardiñas, Jesper Ryge, James T R Walters, Sten Linnarsson, Ed S. Lein, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Patrick F Sullivan, Jens Hjerling-Leffler
bioRxiv 145466; doi: https://doi.org/10.1101/145466

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