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Genetic architecture of host proteins involved in SARS-CoV-2 infection

Published version
Peer-reviewed

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Authors

Carrasco-Zanini, J 
Raffler, J 
Kerrison, ND 

Abstract

Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 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 and evidence that putative viral interaction partners such as MARK3 affect immune 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 detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).

Description

Keywords

ABO Blood-Group System, Aptamers, Peptide, Blood Coagulation, COVID-19, Drug Delivery Systems, Female, Gene Expression Regulation, Host-Derived Cellular Factors, Host-Pathogen Interactions, Humans, Internet, Male, Middle Aged, Proteins, Quantitative Trait Loci, SARS-CoV-2

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Nature Research
Sponsorship
Medical Research Council (MC_UU_12015/1)
MRC (MC_PC_13046)
MRC (MC_UU_00006/1)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046). Proteomic measurements were supported and governed by a collaboration agreement between the University of Cambridge and Somalogic. JCZ and VPWA are supported by a 4-year Wellcome Trust PhD Studentship and the Cambridge Trust, CL, EW, and NJW are funded by the Medical Research Council (MC_UU_12015/1). NJW and ADH are an NIHR Senior Investigator. GK is supported by grants from the National Institute on Aging (NIA): R01 AG057452, RF1 AG058942, RF1 AG059093, U01 AG061359, and U19 AG063744. MR acknowledges funding from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), and the Wellcome Trust (FC001134). ERG is supported by the National Human Genome Research Institute of the National Institutes of Health under Award Numbers R35HG010718 and R01HG011138. JR is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant no. 01ZX1912D). This work was supported by the UCL British Heart Foundation Research Accelerator Award (AA/18/6/34223), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, and arises from one of the national "Covid-19 Cardiovascular Disease Flagship Projects" designated by the NIHR-BHF Cardiovascular Partnership.