Sex-specific exposures and sex-combined outcomes in two-sample Mendelian randomization may mislead the causal inference

With great interest, we have read the recent article “Age at menarche, age at natural menopause, and risk of rheumatoid arthritis — a Mendelian randomization study” by Zhu et al. While we have a great appreciation for the work conducted by the authors, there are some methodological issues that need to be reconsidered. First, the gender description of the sample for age at first birth in this study is wrong according to the original genome-wide association study. Second, the study exploited sex-specific SNPs for age at menarche (AAM) and age at natural menopause (ANM) but sex-combined effects of the SNPs on rheumatoid arthritis (RA) that possibly lead no evidence for the causation of AAM and ANM on RA. We suggested the author add the possible biases due to the issue in the limitations. With problems mentioned above, we recommend solutions to make this article more perfect.