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

## TL;DR

High copper levels in the blood may cause erectile dysfunction, suggesting that managing copper intake could help prevent the condition.

## Contribution

This study provides genetic evidence that elevated copper levels are a causal risk factor for erectile dysfunction.

## Key findings

- Circulating copper levels significantly increased ED risk in discovery, replication, and pooled analyses.
- Sensitivity analyses confirmed the robustness of the findings with no significant heterogeneity or pleiotropy.
- Reverse MR found no causal effect of ED on micronutrient levels, supporting a unidirectional relationship.

## Abstract

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.

Erectile dysfunction (ED) is a common and debilitating condition that negatively impacts men's quality of life and psychological well‐being. Excessive circulating copper levels are causally linked to an increased risk of ED, as shown by Mendelian randomization and meta‐analysis. Balanced copper intake is crucial for sexual health, highlighting the need for careful nutritional management to prevent ED risks.