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Genetic architecture of host proteins interacting with SARS-CoV-2

Maik Pietzner, Eleanor Wheeler, Julia Carrasco-Zanini, Johannes Raffler, Nicola D. Kerrison, Erin Oerton, Victoria P.W. Auyeung, Jian’an Luan, Chris Finan, Juan P. Casas, Rachel Ostroff, Steve A. Williams, View ORCID ProfileGabi Kastenmüller, Markus Ralser, Eric R. Gamazon, View ORCID ProfileNicholas J. Wareham, Aroon D. Hingorani, View ORCID ProfileClaudia Langenberg
doi: https://doi.org/10.1101/2020.07.01.182709
Maik Pietzner
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Eleanor Wheeler
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Julia Carrasco-Zanini
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Johannes Raffler
2Institute of Computational Biology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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Nicola D. Kerrison
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Erin Oerton
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Victoria P.W. Auyeung
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Jian’an Luan
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
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Chris Finan
3Institute of Cardiovascular Science, Faculty of Population Health, University College London, London WC1E 6BT, UK
4UCL BHF Research Accelerator centre
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Juan P. Casas
5Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
6Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA
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Rachel Ostroff
7SomaLogic, Inc., Boulder, CO, USA
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Steve A. Williams
7SomaLogic, Inc., Boulder, CO, USA
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Gabi Kastenmüller
2Institute of Computational Biology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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  • ORCID record for Gabi Kastenmüller
Markus Ralser
8The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
9Department of Biochemistry, Charité University Medicine, Berlin, Germany
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Eric R. Gamazon
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
10Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
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Nicholas J. Wareham
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
11Health Data Research UK, Wellcome Genome Campus and University of Cambridge, UK
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Aroon D. Hingorani
3Institute of Cardiovascular Science, Faculty of Population Health, University College London, London WC1E 6BT, UK
4UCL BHF Research Accelerator centre
12Health Data Research UK, Institute of Health Informatics, University College London, UK
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  • For correspondence: claudia.langenberg@mrc-epid.cam.ac.uk a.hingorani@ucl.ac.uk
Claudia Langenberg
1MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
8The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
11Health Data Research UK, Wellcome Genome Campus and University of Cambridge, UK
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  • ORCID record for Claudia Langenberg
  • For correspondence: claudia.langenberg@mrc-epid.cam.ac.uk a.hingorani@ucl.ac.uk
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ABSTRACT

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid ‘in silico’ assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).

Competing Interest Statement

SW and RO are employees of SomaLogic.

Footnotes

  • https://omicscience.org/apps/covidpgwas/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 01, 2020.
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Genetic architecture of host proteins interacting with SARS-CoV-2
Maik Pietzner, Eleanor Wheeler, Julia Carrasco-Zanini, Johannes Raffler, Nicola D. Kerrison, Erin Oerton, Victoria P.W. Auyeung, Jian’an Luan, Chris Finan, Juan P. Casas, Rachel Ostroff, Steve A. Williams, Gabi Kastenmüller, Markus Ralser, Eric R. Gamazon, Nicholas J. Wareham, Aroon D. Hingorani, Claudia Langenberg
bioRxiv 2020.07.01.182709; doi: https://doi.org/10.1101/2020.07.01.182709
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Genetic architecture of host proteins interacting with SARS-CoV-2
Maik Pietzner, Eleanor Wheeler, Julia Carrasco-Zanini, Johannes Raffler, Nicola D. Kerrison, Erin Oerton, Victoria P.W. Auyeung, Jian’an Luan, Chris Finan, Juan P. Casas, Rachel Ostroff, Steve A. Williams, Gabi Kastenmüller, Markus Ralser, Eric R. Gamazon, Nicholas J. Wareham, Aroon D. Hingorani, Claudia Langenberg
bioRxiv 2020.07.01.182709; doi: https://doi.org/10.1101/2020.07.01.182709

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