Identification of potential drug targets for erectile dysfunction with single-cell RNA sequencing: A Mendelian randomization study.

Background: A subset of patients with erectile dysfunction (ED) responds poorly to current pharmacological treatments, largely due to the limited availability of well-defined therapeutic targets beyond phosphodiesterase 5 inhibitors (PDE5i).

Methods: This study used Mendelian randomization (MR) to identify potential therapeutic targets for ED. Cis-expression quantitative trait loci (cis-eQTL) were sourced from the eQTLGen Consortium (31,684 individuals). ED summary statistics were derived from two cohorts (229,980 individuals: 6175 ED cases, 223,805 controls; 95,178 individuals: 1154 ED cases, 94,024 controls). Co-localization analysis assessed shared single nucleotide polymorphism (SNP) influencing ED risk and gene expression. Drug prediction and molecular docking were utilized to validate the therapeutic potential of the identified drug targets, while single-cell RNA sequencing (scRNA-seq, dataset GSE206528) identified relevant cell types.

Results: Two drug targets demonstrated significance across both cohorts and were corroborated by co-localization analysis. Phenome-wide association studies (PheWAS) revealed no associations with other traits. Molecular docking analysis indicated strong binding affinities between the drugs and proteins. ScRNA-seq results showed the target genes are predominantly expressed in endothelial cells (ECs), Schwann Cells (SWCs)  and smooth muscle cells (SMCs).

Conclusion: This study highlights two promising ED targets, encouraging future research on ECs and SMCs to advance drug development and improve treatment outcomes.