Association of smoking, lung function and COPD in COVID-19 risk: a two-step Mendelian randomization study

Background and Aims Smoking increases the risk of severe COVID-19, but whether lung function or chronic obstructive pulmonary disease (COPD) mediate the underlying associations is unclear. We conducted the largest Mendelian randomization study to date, to our knowledge, to address these questions. Design Mendelian randomization study using summary statistics from genome-wide association studies (GWAS), FinnGen and UK Biobank. The main analysis was the inverse variance weighted method, and we included a range of sensitivity analyses to assess the robustness of the findings. Setting GWAS which included international consortia, FinnGen and UK Biobank. Participants The sample size ranged from 193 638 to 2 586 691. Measurements Genetic determinants of life-time smoking index, lung function [e.g. forced expiratory volume in 1 sec (FEV1)], chronic obstructive pulmonary disease (COPD) and different severities of COID-19. Results Smoking increased the risk of COVID-19 compared with population controls for overall COVID-19 [odds ratio (OR) = 1.19 per standard deviation (SD) of life-time smoking index, 95% confidence interval (CI) = 1.11-1.27], hospitalized COVID-19 (OR = 1.67, 95% CI = 1.42-1.97) or severe COVID-19 (OR = 1.48, 95% CI = 1.10-1.98), with directionally consistent effects from sensitivity analyses. Lung function and COPD liability did not appear to mediate these associations. Conclusion There is genetic evidence that smoking probably increases the risk of severe COVID-19 and possibly also milder forms of COVID-19. Decreased lung function and increased risk of chronic obstructive pulmonary disease do not seem to mediate the effect of smoking on COVID-19 risk.