MR Sensitivity analysis
To assess the robustness of MR effect estimates to potentially invalid
genetic variants, we conducted a sensitivity analysis using the weighted
median and MR-Egger methods when at least five genetic instruments were
available for sex hormones. The weighted median method produced a
consistent causal effect estimate even when up to half of the genetic
variants included in the MR analysis were invalid instrumental variables26. When a weaker assumption (i.e., Instrument
Strength Independent of Direct Effect, INSIDE) was met, the MR-Egger
method was able to estimate causal effects while allowing all SNPs to be
pleiotropic 27.
Previous studies have suggested that obesity may be a potential cause of
COVID-19 susceptibility and
severity 28,29. To minimize the risk of bias resulting
from violating the exclusion restriction assumption (i.e., IVs can only
affect the outcome through exposure rather than alternative pathways),
we identified genome-wide significant SNPs associated with obesity
traits such as BMI and waist-hip ratio based on published GWASs in the
PhenoScanner V2 database
(http://www.phenoscanner.medschl.cam.ac.uk/), and removed these
SNPs from the IVW analysis 30.