Abstract
Observational studies suggest smoking, cannabis use, alcohol consumption, and substance use disorders (SUDs) may impact risk for respiratory infections, including coronavirus 2019 (COVID-2019). However, causal inference is challenging due to comorbid substance use. Using summary-level European ancestry data (>1.7 million participants), we performed single-variable and multivariable Mendelian randomization (MR) to evaluate relationships between substance use behaviors, COVID-19 and other respiratory infections. Genetic liability for smoking demonstrated the strongest associations with COVID-19 infection risk, including the risk for very severe respiratory confirmed COVID-19 (odds ratio (OR) = 2.69, 95% CI, 1.42, 5.10, P-value = 0.002), and COVID-19 infections requiring hospitalization (OR = 3.49, 95% CI, 2.23, 5.44, P-value = 3.74 × 10(-8)); these associations generally remained robust in models accounting for other substance use and cardiometabolic risk factors. Smoking was also strongly associated with increased risk of other respiratory infections, including asthma-related pneumonia/sepsis (OR = 3.64, 95% CI, 2.16, 6.11, P-value = 1.07 × 10(-6)), chronic lower respiratory diseases (OR = 2.29, 95% CI, 1.80, 2.91, P-value = 1.69 × 10(-11)), and bacterial pneumonia (OR = 2.14, 95% CI, 1.42, 3.24, P-value = 2.84 × 10(-4)). We provide strong genetic evidence showing smoking increases the risk for COVID-19 and other respiratory infections even after accounting for other substance use behaviors and cardiometabolic diseases, which suggests that prevention programs aimed at reducing smoking may be important for the COVID-19 pandemic and have substantial public health benefits.