AbstractObjectivesAdiposity, smoking, and lower socioeconomic position (SEP) increase COVID‐19 risk while the association of vitamin D, blood pressure, and glycemic traits in COVID‐19 risk were less clear. Whether angiotensin‐converting enzyme 2 (ACE2), the key receptor for SARS‐CoV‐2, mediates these associations has not been investigated. We conducted a Mendelian randomization study to assess the role of these exposures in COVID‐19 and mediation by ACE2.MethodsWe extracted genetic variants strongly related to various exposures (vitamin D, blood pressure, glycemic traits, smoking, adiposity, and educational attainment [SEP proxy]), and ACE2 cis‐variants from genome‐wide association studies (GWAS, n ranged from 28 204 to 3 037 499) and applied them to GWAS summary statistics of ACE2 (n = 28 204) and COVID‐19 (severe, hospitalized, and susceptibility, n ≤ 2 942 817). We used inverse variance weighted as the main analyses, with MR‐Egger and weighted median as sensitivity analyses. Mediation analyses were performed based on product of coefficient method.ResultsHigher adiposity, lifetime smoking index, and lower educational attainment were consistently associated with higher risk of COVID‐19 phenotypes while there was no strong evidence for an association of other exposures in COVID‐19 risk. ACE2 partially mediates the detrimental effects of body mass index (ranged from 4.3% to 8.2%), waist‐to‐hip ratio (ranged from 11.2% to 16.8%), and lower educational attainment (ranged from 4.0% to 7.5%) in COVID‐19 phenotypes while ACE2 did not mediate the detrimental effect of smoking.ConclusionsWe provided genetic evidence that reducing ACE2 could partly lower COVID‐19 risk amongst people who were overweight/obese or of lower SEP.