ABSTRACT
BACKGROUND: Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity. METHODS: We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase). RESULTS: There were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1-9/day: OR 2.14, 95% CI 0.87 to 5.24; 10-19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72). INTERPRETATION: Congruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.