Cigarette smoking and SARS-CoV-2 infection: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

INTRODUCTION: Evidence of whether smoking affects the risk for SARS-CoV-2 infection is mixed. We aimed to clarify the inconsistencies in previous findings and whether the association is potentially causal using different Mendelian randomization (MR) methods. METHODS: We examined associations between smoking traits (initiation, cessation, and intensity) and SARS-CoV-2 infection in multivariable logistic regression, and one-sample and two-sample MR analyses. The study included n = 47,506 female and n = 28,229 male study subjects from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with questionnaire data and genotype information. SARS-CoV-2 infection status was obtained by data linkage to the national health registry MSIS. RESULTS: We found no clear evidence of an association between smoking initiation and SARS-CoV-2 infection (multivariable regression: OR 1.08, 95% CI 0.96 to 1.20, one-sample multivariable MR analysis: OR 1.02, 95% CI 0.96 to 1.09, two-sample MR: OR 1.10 (95% CI 1.06 to 1.13). Also, we found no clear evidence of an association with smoking intensity (multivariable regression: OR 0.78, 95% CI 0.62 to 0.96, one-sample multivariable MR: OR 1.04, 95% CI 0.76 to 1.42, two-sample MR: OR 1.01, 95% CI 0.95 to 1.09, per 1 SD increase in number of cigarettes per day). Nor was there any association with smoking cessation. These findings did not change after accounting for educational level, BMI or risk-taking behavior in multivariable MR analyses. CONCLUSIONS: We did not find robust evidence of causal associations between smoking and SARS-CoV-2 infection. Our investigation of potential violations to MR assumptions highlights the limitations of this approach to examine infection risk associated with smoking.