Genetically Predicted High IGF-1 Levels Showed Protective Effects on COVID-19 Susceptibility and Hospitalization: A Mendelian Randomisation Study with Data from 60 Studies Across 25 Countries

Background: Epidemiological studies observed gender differences in COVID-19 outcomes, however, whether sex hormone plays a causal in COVID-19 risk remains unclear. This study aimed to examine associations of sex hormone, sex hormones-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1) and COVID-19 risk.Methods: Two-sample Mendelian randomization (TSMR) study was performed to explore the causal associations between testosterone, estrogen, SHBG, IGF-1and the risk of COVID-19 (susceptibility, hospitalization and severity) using GWAS summary level data from the COVID-19 Host Genetics Initiative (N=1,348,701). Random-effects inverse variance weighted (IVW) MR approach was used as the primary MR method and the weighted median, MR-Egger, and MR-PRESSO test were conducted as sensitivity analyses.Findings: Higher genetically predicted IGF-1 levels were significantly associated with reduced risk of COVID-19 susceptibility and hospitalization. For one standard deviation increase in genetically predicted IGF-1 levels, the odds ratio was 0.77 (95% confidence interval [CI], 0.61-0.97; P =0.027) for COVID-19 susceptibility, 0.62 (95%CI: 0.25-0.51; P =0.018) for COVID-19 hospitalization, and 0.85 (95%CI: 0.52-1.38, P =0.513) for COVID-19 severity. There was no evidence that testosterone, estrogen, SHBG are associated with the risk of COVID-19 susceptibility, hospitalization and severity in either overall or sex-stratified TSMR analysis.Interpretation: Genetically predicted high IGF-1 levels may decrease the risk of COVID-19 susceptibility and hospitalization. Further studies are needed to explore whether IGF-1 could be a potential intervention target to reduce COVID-19 risk. Funding: We acknowledge support from NSFC (LR22H260001), CRUK (C31250/A22804), SHLF (Hjärt-Lungfonden, 20210351), VR (Vetenskapsrådet, 2019-00977), and SCI (Cancerfonden).Declaration of Interest: All authors declare no conflict of interest.