Genetic association between COVID-19 and male infertility: a two-sample Mendelian randomization analysis

The impact of COVID-19 on male reproductive function has been widely reported, but the underlying genetic basis of this relationship remains unclear. A new and useful method for exploring causal associations between exposures and outcomes is Mendelian randomization (MR), which utilizes genetic variants, also known as single nucleotide polymorphisms (SNPs), as instrumental variables (IVs) in a retrospective way. In this study, a two -sample MR analysis was conducted to investigate the potential causal effect of COVID-19 on male infertility using summary -level data from largescale genome-wide association studies (GWAS). SNPs identified in the COVID-19 and male infertility GWAS were used as IVs, and the causal effect was estimated using three methods: inverse -variance weighted (IVW), weighted median, and MREgger regression. Additionally, a leave -one -out analysis was performed as a sensitivity analysis to assess the robustness of the findings. The exposures to COVID-19 were obtained from the largest and most recent GWAS, which included 9986 cases versus 1,877,672 controls for hospitalized patients and 5101 cases versus 1,383,241 controls of severe patients of European ancestry. The corresponding outcome for male infertility was also obtained from the largest and most recent GWAS meta -analysis of 680 cases and 72,799 controls of European ancestry. The results based on the three methods showed no significant association between hospitalized or severe COVID-19 and male infertility. Specifically, the odds ratio for IVW was 0.86 (95% confidence interval (CI): 0.65- 1.15, p = 0.308), 0.96 (95% CI: 0.54-1.69, p = 0.886) for MR -Egger, and 0.87 (95% CI: 0.62-1.22, p = 0.430) for weighted median. These findings suggest that COVID19 may have no causal effect on male reproductive function, although further studies are needed to validate these results. The present study provides evidence for a genetic association between COVID-19 (including both hospitalized and severe COVID-19) and male infertility.