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Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

View ORCID ProfileKatia de Paiva Lopes, View ORCID ProfileGijsje J. L. Snijders, View ORCID ProfileJack Humphrey, View ORCID ProfileAmanda Allan, Marjolein Sneeboer, View ORCID ProfileElisa Navarro, View ORCID ProfileBrian M. Schilder, View ORCID ProfileRicardo A. Vialle, View ORCID ProfileMadison Parks, Roy Missall, Welmoed van Zuiden, Frederieke Gigase, Raphael Kübler, Amber Berdenis van Berlekom, View ORCID ProfileChotima Böttcher, View ORCID ProfileJosef Priller, View ORCID ProfileRené S. Kahn, View ORCID ProfileLot D. de Witte, View ORCID ProfileTowfique Raj
doi: https://doi.org/10.1101/2020.10.27.356113
Katia de Paiva Lopes
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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  • ORCID record for Katia de Paiva Lopes
Gijsje J. L. Snijders
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
6Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, New York City, NY, United States of America
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Jack Humphrey
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Amanda Allan
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Marjolein Sneeboer
7Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands
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Elisa Navarro
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Brian M. Schilder
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Ricardo A. Vialle
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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  • ORCID record for Ricardo A. Vialle
Madison Parks
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Roy Missall
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
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Welmoed van Zuiden
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
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Frederieke Gigase
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
6Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, New York City, NY, United States of America
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Raphael Kübler
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
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Amber Berdenis van Berlekom
7Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands
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Chotima Böttcher
8Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
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Josef Priller
8Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
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René S. Kahn
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
6Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, New York City, NY, United States of America
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Lot D. de Witte
5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States of America
6Mental Illness Research, Education and Clinical Center (MIRECC), James J Peters VA Medical Center, New York City, NY, United States of America
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  • For correspondence: lotje.dewitte@mssm.edu towfique.raj@mssm.edu
Towfique Raj
1Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
2Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
3Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
4Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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  • For correspondence: lotje.dewitte@mssm.edu towfique.raj@mssm.edu
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Abstract

Microglial cells have emerged as potential key players in brain aging and pathology. To capture the heterogeneity of microglia across ages and regions, and to understand how genetic risk for neurological and psychiatric brain disorders is related to microglial function, large transcriptome studies are essential. Here, we describe the transcriptome analysis of 255 primary human microglia samples isolated at autopsy from multiple brain regions of 100 human subjects. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region, age and sex. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, including novel associations with microglia expression of USP6NL for Alzheimer’s disease, and P2RY12 for Parkinson’s disease. In summary, we have built the most comprehensive catalog to date of genetic effects on the microglia transcriptome and propose molecular mechanisms of action of candidate functional variants in several neurological and psychiatric diseases.

Competing Interest Statement

The authors have declared no competing interest.

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Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies
Katia de Paiva Lopes, Gijsje J. L. Snijders, Jack Humphrey, Amanda Allan, Marjolein Sneeboer, Elisa Navarro, Brian M. Schilder, Ricardo A. Vialle, Madison Parks, Roy Missall, Welmoed van Zuiden, Frederieke Gigase, Raphael Kübler, Amber Berdenis van Berlekom, Chotima Böttcher, Josef Priller, René S. Kahn, Lot D. de Witte, Towfique Raj
bioRxiv 2020.10.27.356113; doi: https://doi.org/10.1101/2020.10.27.356113
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Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies
Katia de Paiva Lopes, Gijsje J. L. Snijders, Jack Humphrey, Amanda Allan, Marjolein Sneeboer, Elisa Navarro, Brian M. Schilder, Ricardo A. Vialle, Madison Parks, Roy Missall, Welmoed van Zuiden, Frederieke Gigase, Raphael Kübler, Amber Berdenis van Berlekom, Chotima Böttcher, Josef Priller, René S. Kahn, Lot D. de Witte, Towfique Raj
bioRxiv 2020.10.27.356113; doi: https://doi.org/10.1101/2020.10.27.356113

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