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Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study

International Journal of Impotence Research volume 37, pages 601–611 (2025)Cite this article

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Abstract

Erectile dysfunction is a common sexual disorder in men. Some studies have found a strong association between some serum metabolites and erectile dysfunction. To investigate this association further, we used bidirectional Mendelian randomisation to investigate causality and possible biological mechanisms.Firstly, this study screened the statistics of genome-wide association studies of serum metabolites and erectile dysfunction to obtain instrumental variables. Inverse variance weighting was used as the primary method for causal effect analysis of instrumental variables in forward or reverse Mendelian randomisation, and the results obtained by MR-Egger regression and the weighted median method were used as references. Subsequently, the metabolites causally associated with erectile dysfunction were subjected to replication analyses and meta-analyses, and the results of the meta-analyses were analysed by pathway analyses to find influential pathways. In this process, Mendelian randomisation results need to be assessed for stability and reliability using sensitivity analysis.It was found that a total of six serum metabolites were causally associated with erectile dysfunction in a forward Mendelian randomisation study. 1,3,7-trimethyluraten (0.85 (0.73–0.99), P = 0.0368), ergothioneine (0.65 (0.45–0.94), P = 0.0226) and gamma-glutamylglutamate (0.63 (0.46–0.88), P = 0.0059) were protective against the development of erectile dysfunction, whereas 2-hydroxyhippurate (1.10 (1.02–1.19), P = 0.0152), N2,N2-dimethylguanosine (1.57 (1.02–2.40), P = 0.0395) and octanoylcarnitine (1.38 (1.06–1.82), P = 0.0183) were able to induce the development of erectile dysfunction. In addition, metabolic pathway analysis showed that 1,3,7-trimethylurate was able to influence the development of erectile dysfunction via the caffeine metabolism pathway (P = 0.0454). On the other hand, reverse Mendelian randomisation analysis showed that erectile dysfunction reduced serum homocitrulline levels (0.99 (0.97–1.00), P = 0.0360). Sensitivity analyses, including heterogeneity tests and pleiotropy tests, confirmed the reliability of the results.In conclusion, this study demonstrated a bidirectional causal relationship between serum metabolites and erectile dysfunction using bidirectional Mendelian randomisation analysis and replication meta-analysis. On this basis, this study provides a new direction of thinking and strong evidence for the therapeutic application and adjunctive diagnosis of serum metabolites in erectile dysfunction, and provides a certain reference value for subsequent related studies.

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Fig. 1: The overall flowchart of the study.
Fig. 2: Forest plot of the causal effects of metabolites on the risk of ED derived from the IVW method.
Fig. 3: Forest plot for forward MR replication analysis.
Fig. 4: Forest plots of the meta-analysis of each of the 10 metabolites in the forward MR.
Fig. 5: Forest plot of the causal effects of ED on the risk of metabolites derived from the IVW method.
Fig. 6: Forest plots for reverse MR replication analysis. (MR: Mendelian randomisation.
Fig. 7: Forest plots of the meta-analysis of each of the 6 metabolites in the reverse MR.

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Data availability

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.

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Acknowledgements

We thank all the participants and investigators of the IEU consortium, FinnGen consortium and Metabolomics GWAS.

Funding

This work was supported the Young/Middle aged Talent Cultivation Project that was funded by the Fujian Provincial Health and Family Planning Commission and Xiamen Health and Family Planning Commission (No. 2021GGB028).

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Authors and Affiliations

  1. Department of Urology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Ran Xu, Shuo Liu, Lu-yi Li, Yue Bu, Pei-ming Bai, Guang-cheng Luo & Xin-jun Wang

  2. Department of Urology, Zhongshan Hospital Xiamen University, The School of Clinical Medicine, Fujian Medical University, Xiamen, China

    Guang-cheng Luo & Xin-jun Wang

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  1. Ran Xu
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Contributions

RX and XW designed the study, contributed to the data analysis, and wrote the manuscript. SL, LL and YB contributed to the data analysis and data interpretation. PB and GL contributed to manuscript writing and revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xin-jun Wang.

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Xu, R., Liu, S., Li, Ly. et al. Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study. Int J Impot Res 37, 601–611 (2025). https://doi.org/10.1038/s41443-024-00926-2

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