BackgroundThe causal relationship between hypertension, antihypertensive drugs and the risk of erectile dysfunction is still uncertain. We performed a univariable and multivariable Mendelian randomization study to investigate whether they are causally related to erectile dysfunction.MethodsGenetic variants associated with blood pressure were derived from the genome-wide association study meta-analysis of the UK Biobank and International Consortium of Blood Pressure (N= 757,601). Summary association data for hypertension were obtained from the UK Biobank (N= 463,010) and the FinnGen study (N= 356,077). The summary statistics of erectile dysfunction were obtained from the European ancestry with 223,805 subjects. The SNP instruments used to assess the effect of the protein targets of antihypertensive drugs on erectile dysfunction were obtained from previous studys. Causal effects were estimated using the univariate Mendelian randomization method (inverse variance weighted, MR-Egger, weighted median, MR-PRESSO and Wald ratios) and the multivariate Mendelian randomization method. Sensitivity analyses were implemented with the Cochran'sQ-test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis.ResultsUnivariate MR found that elevated diastolic blood pressure may increase the occurrence of erectile dysfunction (odds ratio [OR] = 1.012; 95% confidence interval [CI]: 1.000–1.024;P= 0.047). Genetically predicted hypertension is also associated with ED (For the FinnGen, OR = 1.106; 95% CI: 1.027–1.191;P= 0.008. For the UK Biobank, OR = 3.832; 95% CI: 1.410–10.414;P= 0.008). However, after adjusting for systolic blood pressure, diastolic blood pressure and hypertension using multivariate Mendelian randomization, only hypertension was causally associated with ED occurrence (For the FinnGen, OR = 1.103; 95% CI: 1.018–1.195;P= 0.017. For the UK Biobank, OR = 5.037; 95% CI: 1.601–15.846;P= 0.006). We found no evidence that the use of angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and thiazide diuretic increased the risk of erectile dysfunction.ConclusionsGenetically predicted hypertension increases the risk of erectile dysfunction, but we found no causal relationship between elevated systolic/diastolic blood pressure and erectile dysfunction. We speculate that the relationship between elevated blood pressure and erectile dysfunction risk may be nonlinear. We found little evidence that antihypertensive drugs increase the risk of erectile dysfunction.