1. Epidemiology and Global Health
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Mendelian randomization analysis provides causality of smoking on the expression of ACE2, a putative SARS-CoV-2 receptor

  1. Hui Liu
  2. Junyi Xin
  3. Sheng Cai
  4. Xia Jiang  Is a corresponding author
  1. Zhejiang University, China
  2. Nanjing Medical University, China
  3. Karolinska Institutet, Sweden
Research Article
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Cite this article as: eLife 2021;10:e64188 doi: 10.7554/eLife.64188


Background: To understand a causal role of modifiable lifestyle factors in ACE2 expression (a putative SARS-CoV-2 receptor) across 44 human tissues/organs, and in COVID-19 susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study.

Methods: More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median and MR-PRESSO were performed to identify potential horizontal pleiotropy.

Results: We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (β=1.468, p=1.8 10-8); and increased ACE2 expression in adipose, brain, colon and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7 10-5). No statistically significant result was observed for alcohol consumption.

Conclusions: Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19.

Funding: Dr. Jiang is supported by research grants from the Swedish Research Council (VR-2018-02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020-00884).

Data availability

Data and main programming codes with annotations have been uploaded to GitHub and made publicly available at https://github.com/hye-hz/MR_Smoke_COVID19.git.

The following previously published data sets were used

Article and author information

Author details

  1. Hui Liu

    Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5531-3640
  2. Junyi Xin

    Department of Environmental Genomics, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6677-3936
  3. Sheng Cai

    Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xia Jiang

    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5878-8986


Swedish Research Council (VR-2018-02247)

  • Xia Jiang

Swedish Research Council for Health, Working Life and Welfare (FORTE-2020-00884)

  • Xia Jiang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. M Dawn Teare, Newcastle University, United Kingdom

Publication history

  1. Received: October 20, 2020
  2. Accepted: June 19, 2021
  3. Accepted Manuscript published: July 6, 2021 (version 1)
  4. Version of Record published: July 15, 2021 (version 2)


© 2021, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Further reading

Further reading

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    The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19.


    To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets.


    Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19.


    Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.


    MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.