Sex-specific causal effects of serum sex hormones on COVID-19 susceptibility and severity: evidence from the UK Biobank and COVID-19 Host Genetics Initiative

Objectives: Several medications and treatments are being investigated for their potential effectiveness against coronavirus disease 2019 (COVID-19), including androgen and other sex hormones. However, the causal relationships between serum sex hormones and COVID-19 susceptibility and severity, particularly with regards to potentially sex-specific effects, remain largely unknown.Methods: In this study, we used the latest data from the UK Biobank (up to 424,907 individuals) and COVID-19 Host Genetics Initiative (up to 1,878,143 individuals) to systematically assess the sex-specific causal effects of serum sex hormone levels on COVID-19 outcomes within a two-sample Mendelian randomization (MR) framework. The inverse-variance weighted method was used in the main MR analysis. We additionally performed a series of sensitivity analysis to assess the robustness of MR effect estimates to potentially invalid genetic variants.Results: Our MR analysis revealed novel causal associations between serum estradiol and bioavailable testosterone levels and SARS-CoV-2 infection in women, but not men, except for a suggestive inverse causal association between estradiol levels and COVID-19 severity in men.Conclusions: These novel findings improve our understanding of the sex-specific causal nature of sex hormones in relation to COVID-19 outcomes, and suggest that sex hormones may serve as potential therapeutic targets for preventing SARS-CoV-2 infection and improving patient outcomes.Funding: This project was supported by the Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [grant number 2021YJRC02]; the National Natural Science Foundation of China [grant number 82103949]; and the Applied Basic Research Project of Shanxi Province, China [grant number 20210302124186].Declaration of Interest: The authors declare no conflict of interest.