Mendelian randomization analysis provides causality of smoking on the expression of ACE2, a putative SARS-CoV-2 receptor

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Abstract

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

1. Liu M et al
(2019) Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use
doi: 10.1038/s41588-018-0307-5.

https://genome.psych.umn.edu/index.php/GSCAN
1. GTEx Consortium
(2017) Genetic effects on gene expression across human tissues
doi: 10.1038/nature24277.

https://www.gtexportal.org
1. COVID-19 Host Genetics Initiative
(2020) COVID-19 Host Genetics Initiative
doi: 10.1038/s41431-020-0636-6.

https://www.covid19hg.org/results/

Article and author information

Author details

Hui Liu

Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Zhejiang University, Hangzhou, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5531-3640
Junyi Xin

Department of Environmental Genomics, Nanjing Medical University, Nanjing, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6677-3936
Sheng Cai

Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang University, Hangzhou, China

Competing interests
The authors declare that no competing interests exist.
Xia Jiang

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

For correspondence
xia.jiang@ki.se

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5878-8986

Funding

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.

Copyright

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.