Objectives: We assessed the causal association of three COVID-19 phenotypes with insulin-like growth factor 1 (IGF-1), estrogen, testosterone, dehydroepiandrosterone (DHEA), thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Methods: We used a bidirectional two-sample univariate and multivariable Mendelian randomization (MR) analysis to evaluate the direction, specificity, and causality of the association between CNS-regulated hormones and COVID-19 phenotypes. Genetic instruments for CNS-regulated hormones were selected from the largest publicly available genome-wide association studies in the European population. Summary-level data on COVID-19 severity, hospitalization, and susceptibility were obtained from the COVID-19 host genetic initiative. Results: DHEA was associated with increased risks of very severe respiratory syndrome (OR=4.21, 95% CI: 1.41-12.59), consistent with the results in multivariate MR (OR=3.72, 95% CI: 1.20-11.51), and hospitalization (OR = 2.31, 95% CI: 1.13-4.72) in univariate MR. LH was associated with very severe respiratory syndrome (OR=0.83; 95% CI: 0.71-0.96) in univariate MR. Estrogen was negatively associated with very severe respiratory syndrome (OR=0.09, 95% CI: 0.02-0.51), hospitalization (OR=0.25, 95% CI: 0.08-0.78), and susceptibility (OR=0.50, 95% CI: 0.28-0.89) in multivariate MR. Conclusions: We found strong evidence for the causal relationship of DHEA, LH, and estrogen with COVID-19 phenotypes.

The authors have declared no competing interest.

This study is supported by the Research Start-up Fund of the Seventh Affiliated Hospital, Sun Yat-sen University (Grant No. 392016).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The source data were openly available before the study conducted and could be found as following: GWAS summary data of seven hormone traits are available in IEU open GWAS project (https://gwas.mrcieu.ac.uk/). GWAS summary data of TSH are collected in a GWAS meta-analysis of thyroid-related traits. Summary statistics (release 5) of GWAS meta-analysis for the three COVID-19 phenotypes are available in the COVID-19 Host Genetics Initiative (HGI) at https://www.covid19hg.org/results/r5/.

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GWAS summary data of seven hormone traits are available in IEU open GWAS project (https://gwas.mrcieu.ac.uk/) with GWAS ID as ukb-d-30770_irnt for IGF-1, ukb-d-30800_irnt for Estradiol, ukb-d-30850_irnt for Testosterone, met-a-478 for DHEA-S, prot-a-3102 for TRH, prot-a-529 for LH, and prot-c-3032_11_2 for FSH. GWAS summary data of TSH are collected in a GWAS meta-analysis of thyroid-related traits. Summary statistics (release 5) of GWAS meta-analysis for the three COVID-19 phenotypes are available in the COVID-19 Host Genetics Initiative (HGI) at https://www.covid19hg.org/results/r5/.

https://gwas.mrcieu.ac.uk/