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Genetic Identification of Cell Types Underlying Brain Complex Traits Yields Novel Insights Into the Etiology of Parkinson’s Disease

View ORCID ProfileJulien Bryois, Nathan G. Skene, Thomas Folkmann Hansen, Lisette J.A. Kogelman, Hunna J. Watson, Eating Disorders Working Group of the Psychiatric Genomics Consortium, International Headache Genetics Consortium, The 23andMe Research Team, Leo Brueggeman, Gerome Breen, Cynthia M. Bulik, Ernest Arenas, Jens Hjerling-Leffler, Patrick F. Sullivan
doi: https://doi.org/10.1101/528463
Julien Bryois
1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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  • ORCID record for Julien Bryois
Nathan G. Skene
2Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
3UCL Institute of Neurology, Queen Square, London, UK
4Division of Brain Sciences, Department of Medicine, Imperial College, London, UK
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Thomas Folkmann Hansen
5Danish Headache Center, Dept. of Neurology, Copenhagen University Hospital, Glostrup, Denmark
6Institute of Biological Psychiatry, Copenhagen University Hospital MHC Sct. Hans, Roskilde, Denmark
7Novo Nordic Foundations Center for Protein Research, Copenhagen University, Denmark.
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Lisette J.A. Kogelman
5Danish Headache Center, Dept. of Neurology, Copenhagen University Hospital, Glostrup, Denmark
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Hunna J. Watson
8Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, US
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923andMe, Inc., Mountain View, CA, 94041, USA
Leo Brueggeman
10Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa.
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Gerome Breen
11Institute of Psychiatry, Psychology and Neuroscience, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, King’s College London, London, UK
12National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, UK
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Cynthia M. Bulik
1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
8Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, US
13Department of Nutrition, University of North Carolina, Chapel Hill, NC, 27599-7264, USA
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Ernest Arenas
2Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Jens Hjerling-Leffler
2Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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  • For correspondence: jens.hjerling-leffler@ki.se patrick.sullivan@ki.se
Patrick F. Sullivan
1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
14Departments of Genetics, University of North Carolina, Chapel Hill, NC, 27599-7264, USA
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  • For correspondence: jens.hjerling-leffler@ki.se patrick.sullivan@ki.se
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Abstract

Genome-wide association studies (GWAS) have discovered hundreds of loci associated with complex brain disorders, and provide the best current insights into the etiology of these idiopathic traits. However, it remains unclear in which cell types these variants may be active, which is essential for understanding disease etiology and for disease modelling. Here we integrate GWAS results with single-cell transcriptomic data from the entire nervous system to systematically identify cell types underlying psychiatric disorders, neurological conditions, and other brain complex traits. We show that psychiatric disorders are predominantly associated with excitatory neurons from the cortex/hippocampus, medium spiny neurons from the striatum, diverse sets of midbrain neurons, and inhibitory neurons from the cortex/hippocampus. Cognitive traits were generally associated with similar cell types but their associations were driven by different genes. Neurological disorders were associated with different cell types, consistent with other lines of evidence. Notably, we found that Parkinson’s disease is not only genetically associated with dopaminergic neurons but also with serotonergic neurons and cells from the oligodendrocyte lineage. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Altogether, our study provides a solid framework for understanding the cellular basis of complex brain disorders and reveals a new unexpected role of oligodendrocytes in Parkinson’s disease.

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Posted January 23, 2019.
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Genetic Identification of Cell Types Underlying Brain Complex Traits Yields Novel Insights Into the Etiology of Parkinson’s Disease
Julien Bryois, Nathan G. Skene, Thomas Folkmann Hansen, Lisette J.A. Kogelman, Hunna J. Watson, Eating Disorders Working Group of the Psychiatric Genomics Consortium, International Headache Genetics Consortium, The 23andMe Research Team, Leo Brueggeman, Gerome Breen, Cynthia M. Bulik, Ernest Arenas, Jens Hjerling-Leffler, Patrick F. Sullivan
bioRxiv 528463; doi: https://doi.org/10.1101/528463
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Genetic Identification of Cell Types Underlying Brain Complex Traits Yields Novel Insights Into the Etiology of Parkinson’s Disease
Julien Bryois, Nathan G. Skene, Thomas Folkmann Hansen, Lisette J.A. Kogelman, Hunna J. Watson, Eating Disorders Working Group of the Psychiatric Genomics Consortium, International Headache Genetics Consortium, The 23andMe Research Team, Leo Brueggeman, Gerome Breen, Cynthia M. Bulik, Ernest Arenas, Jens Hjerling-Leffler, Patrick F. Sullivan
bioRxiv 528463; doi: https://doi.org/10.1101/528463

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