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. Biomedical Research Center, Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China
  2. Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, China
  3. Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, China
  4. Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Sweden
Research Article
Cite this article as: eLife 2021;10:e64188 doi: 10.7554/eLife.64188
5 figures, 3 tables and 2 additional files

Figures

Flowchart on the selection of instrumental variables.
Appendix 1—figure 1
Leave-one-out analysis of causal association of smoking initiation with angiotensin-converting enzyme 2 (ACE2) expression.

Each boxplot represents the centralized tendency of effect sizes (beta coefficients) of smoking initiation on tissue-specific ACE2 expression based on the results of leave-one-out analysis where we excluded one single nucleotide polymorphism (SNP) at a time and performed inverse-variance weighted (IVW) using the remaining SNPs.

Appendix 1—figure 2
Leave-one-out analysis of causal association of cigarettes per day with angiotensin-converting enzyme 2 (ACE2) expression.

Each boxplot represents the centralized tendency of effect sizes (beta coefficients) of cigarettes per day on tissue-specific ACE2 expression based on the results of leave-one-out analysis where we excluded one single nucleotide polymorphism (SNP) at a time and performed inverse-variance weighted (IVW) using the remaining SNPs.

Appendix 1—figure 3
Leave-one-out analysis of causal association of drinks per week with angiotensin-converting enzyme 2 (ACE2) expression.

Each boxplot represents the centralized tendency of effect sizes (beta coefficients) of drinks per week on tissue-specific ACE2 expression based on the results of leave-one-out analysis where we excluded one single nucleotide polymorphism (SNP) at a time and performed inverse-variance weighted (IVW) using the remaining SNPs.

Appendix 1—figure 4
Leave-one-out analysis of causal association of smoking and alcohol consumption with coronavirus disease 2019 (COVID-19) related adverse outcomes.

(A) Leave-one-out analysis of causal association of smoking initiation with COVID-19 related adverse outcomes. (B) Leave-one-out analysis of causal association of cigarettes per day with COVID-19 related adverse outcomes. (C) Leave-one-out analysis of causal association of drinks per week with COVID-19 related adverse outcomes. Each boxplot represents the centralized tendency of effect sizes (beta coefficients) of exposure (including smoking and alcohol consumption) on COVID-19 related adverse outcomes based on the results of leave-one-out analysis where we excluded one single nucleotide polymorphism (SNP) at a time and performed inverse-variance weighted (IVW) using the remaining SNPs. COVID-19 indicates susceptibility to COVID-19. Severe COVID-19 indicates very severe respiratory confirmed COVID-19.

Tables

Table 1
Causal association of smoking initiation and angiotensin-converting enzyme 2 (ACE2) expression.
Organ/tissueMethodN of IVsBetaSEpp*
Adipose – subcutaneousInverse-variance weighted3580.2850.1180.0160.834
MR-Egger3580.6630.5220.2050.456
Weighted median3580.1420.1860.444
MR-PRESSO3580.2850.1180.0170.846
Brain – hypothalamusInverse-variance weighted3560.8480.3690.0220.614
MR-Egger3560.9631.5880.5450.941
Weighted median3560.5490.5660.332
MR-PRESSO3560.8480.3690.0220.655
Brain – putamen
(basal ganglia)
Inverse-variance weighted3571.1170.4060.0060.334
MR-Egger3571.6671.7240.3340.743
Weighted median3571.2560.6070.039
MR-PRESSO3571.1170.4060.0060.321
Colon – sigmoidInverse-variance weighted3590.3140.2140.1430.887
MR-Egger3591.9250.9450.0420.080
Weighted median3590.4730.3340.156
MR-PRESSO3590.3140.2140.1440.904
Colon – transverseInverse-variance weighted3590.1930.1130.0880.348
MR-Egger3591.1290.4710.0170.041
Weighted median3590.2620.1650.114
MR-PRESSO3590.1930.1130.0890.362
  1. *p indicates p-value of heterogenous from inverse-variance weighted (IVW) approach, or p-value of intercept from MR-Egger regression, or p-value from Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test.

Table 2
Causal association of cigarettes per day and angiotensin-converting enzyme 2 (ACE2) expression.
Organ/tissueMethodN of IVsBetaSEpp*
Brain – hypothalamusInverse-variance weighted481.7890.7300.0140.959
MR-Egger480.0411.9200.9830.310
Weighted median482.1821.3470.105
MR-PRESSO481.7890.7300.0180.964
Colon – sigmoidInverse-variance weighted47−0.8320.4390.0580.652
MR-Egger47−1.9710.8070.0190.092
Weighted median47−1.1820.7470.114
MR-PRESSO47−0.8320.4390.0640.701
LiverInverse-variance weighted471.2160.4680.0090.807
MR-Egger471.1320.9220.2260.913
Weighted median471.0580.8500.213
MR-PRESSO471.2160.4680.0120.843
OvaryInverse-variance weighted481.5450.6930.0260.837
MR-Egger481.6581.7450.3470.943
Weighted median482.5451.2170.037
MR-PRESSO481.5450.6930.0310.844
ThyroidInverse-variance weighted471.4680.3921.8×10−40.604
MR-Egger471.7390.9070.0620.739
Weighted median471.4350.6410.025
MR-PRESSO471.4680.3925.0×10−40.670
VaginaInverse-variance weighted48−1.1500.6880.0940.055
MR-Egger48−3.2711.5740.0430.142
Weighted median48−2.6440.9160.004
MR-PRESSO48−1.1500.6880.1010.057
  1. *p indicates p-value of heterogenous from inverse-variance weighted (IVW) approach, or p-value of intercept from MR-Egger regression, or p-value from Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test.

Table 3
Causal link of smoking initiation with the risk of coronavirus disease 2019 (COVID-19) related adverse outcomes.
OutcomeMethodN of IVsOR (95% CI)pp*
COVID-19 susceptibilityInverse-variance weighted3521.15 (1.07–1.23)8.7×10−56.7×10−5
MR-Egger3521.11 (0.83–1.49)0.4890.821
Weighted median3521.18 (1.08–1.29)2.9×10−4
MR-PRESSO3521.15 (1.07–1.23)1.0×10−45.0×10−5
Hospitalized COVID-19Inverse-variance weighted3511.32 (1.16–1.50)3.7×10−50.009
MR-Egger3510.78 (0.44–1.36)0.3830.059
Weighted median3511.37 (1.14–1.66)0.001
MR-PRESSO3511.32 (1.16–1.50)4.6×10−50.011
Very severe respiratory confirmed COVID-19Inverse-variance weighted3521.25 (1.03–1.51)0.0250.114
MR-Egger3520.83 (0.37–1.89)0.6580.318
Weighted median3521.17 (0.89–1.55)0.267
MR-PRESSO3521.25 (1.03–1.51)0.0250.119
  1. *p indicates p-value of heterogeneous from inverse-variance weighted (IVW) approach, or p-value of intercept from MR-Egger regression, or p-value from Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test.

Additional files

Supplementary file 1

Supplementary results of the causality of smoking and alcohol consumption on angiotensin-converting enzyme 2 (ACE2) expression and coronavirus disease 2019 (COVID-19) related outcomes.

(a) Information of genome-wide significant single nucleotide polymorphisms (SNPs) associated with smoking initiation. (b) Information of genome-wide significant SNPs associated with cigarettes per day. (c) Information of genome-wide significant SNPs associated with drinks per week. (d) Sample size of ACE2 expression in 44 tissues/organs from GTEx database. (e) Statistical power in Mendelian randomization study on causal association of smoking and alcohol consumption with ACE2 expression andCOVID-19 related adverse outcomes. (f) Causal association of smoking initiation and ACE2 expression. (g) Causal association of cigarettes per day and ACE2 expression. (h) Causal association of drinks per week and ACE2 expression. (i) Causal association of smoking initiation and ACE2 expression excluding palindromic SNPs. (j) Causal association of cigarettes per day and ACE2 expression excluding palindromic SNPs. (k) Causal association of drinks per week and ACE2 expression excluding palindromic SNPs. (l) Causal association of smoking initiation and ACE2 expression excluding pleiotropic SNPs. (m) Causal association of cigarettes per day and ACE2 expression excluding pleiotropic SNPs. (n) Causal association of drinks per week and ACE2 expression excluding pleiotropic SNPs. (o) Causal association of cigarettes per day with the risk of COVID-19 related adverse outcomes. (p) Causal association of drinks per week with the risk of COVID-19 related adverse outcomes. (q) Causal association of smoking and alcohol consumption with the risk of COVID-19 related adverse outcomes excluding palindromic SNPs. (r) Causal association of smoking and alcohol consumption with the risk of COVID-19 related adverse outcomes excluding pleiotropic SNPs.

https://cdn.elifesciences.org/articles/64188/elife-64188-supp1-v2.xlsx
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