Causal Inference of CNS-regulated Hormones in COVID-19: A Bidirectional Two-sample Mendelian Randomization Study

ObjectivesWe 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). MethodsWe 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. ResultsDHEA 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. ConclusionsWe found strong evidence for the causal relationship of DHEA, LH, and estrogen with COVID-19 phenotypes.