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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Julien Bryois, Karolinska Institutet
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  • Nathan G Skene, Karolinska Institutet, UCL Institute of Neurology, Imperial College
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  • Thomas Folkmann Hansen, University of Copenhagen, MHC Sct. Hans
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  • Lisette J A Kogelman, University of Copenhagen
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  • Hunna J Watson, University of North Carolina at Chapel Hill, Curtin University, The University of Western Australia
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  • Zijing Liu, Imperial College
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  • Leo Brueggeman, University of Iowa
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  • Gerome Breen, National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, UK., King’s College London
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  • Cynthia M Bulik, Karolinska Institutet, University of North Carolina at Chapel Hill, University of North Carolina
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  • Ernest Arenas, Karolinska Institutet
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  • Jens Hjerling-Leffler, Karolinska Institutet
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  • Patrick F Sullivan, Karolinska Institutet, University of North Carolina
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  • Eating Disorders Working Group of the Psychiatric Genomics Consortium

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.

Original languageEnglish
JournalNature Genetics
Pages (from-to)482-493
Number of pages12
Publication statusPublished - May 2020

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