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

Abstract

AbstractObjectivesWe 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.