Unraveling the Causal Association Between Circulating Copper Levels and Erectile Dysfunction: A Comprehensive Analysis via Bidirectional Two Sample Mendelian Randomization Study

Erectile dysfunction (ED) is a prevalent condition severely impacting men's quality of life. While micronutrient balance is critical for sexual health, observational studies on micronutrient and ED remain inconclusive. The objective of this study was to evaluate the causal role of circulating levels of copper and other micronutrients in ED risk by Mendelian randomization (MR). We conducted bidirectional two-sample MR using summary statistics from European-ancestry cohorts involving thirteen micronutrients. Inverse-variance weighted (IVW) MR was complemented by sensitivity analyses, including MR-Egger and MR-PRESSO, and pooled analysis of two GWAS-based datasets was performed to substantiate the findings of MR. In this study, circulating copper levels significantly increased ED risk in the discovery (OR = 1.129, 95% CI: 1.004–1.27, p = 0.042) and replication (OR = 1.115, 95% CI: 1.001–1.242, p = 0.0476) stages, as well as pooled analyses (OR = 1.122, 95% CI: 1.036–1.214, p = 0.0046). Sensitivity analyses reinforced the robustness of these findings, with no significant heterogeneity or directional pleiotropy observed. Reverse MR found no causal effect of ED on micronutrients. In summary, this study provides robust genetic evidence that elevated circulating copper levels are a modifiable risk factor for ED. Personalized management of copper intake, guided by genetic predisposition, may mitigate ED risk and improve sexual health outcomes. These findings highlight the clinical relevance of copper homeostasis in ED prevention and underscore the need for targeted nutritional interventions.