Identification of Novel Disease-Modifying Agents for Pelvic Organ Prolapse by Systematic Druggable Genome-Wide Mendelian Randomization

Xiaochun Liu,1,* Zongyu Zhao,2,* Lin Wang2 1Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China; 2Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaochun Liu, Department of Gynaecology and Obstetrics, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China, Email [email protected]: Pelvic organ prolapse (POP) present a significant global health burden, yet effective therapeutic targets remain limited. This study aims to identify potential disease-modifying agents for POP and provide insights to guide the development of targeted therapeutics.Methods: We integrated data from the druggable genome and expression quantitative trait loci (eQTL) with genome-wide association studies (GWAS) and employed Mendelian randomisation (MR) alongside colocalization analysis to identify potential therapeutic targets. To further elucidate the biological relevance of the identified targets, we performed functional enrichment analyses, including the construction of protein-protein interaction (PPI) networks, Gene Ontology (GO) annotations, and KEGG pathway analysis. Key candidate genes were subsequently evaluated using phenome-wide MR (Phe-MR) to investigate potential adverse effects of these druggable genes on POP treatment.Results: From two druggable gene sets, two QTLs datasets, four different tissues, and two large-scale POP GWAS datasets, we identified 23 positive targets and 5 druggable genes, including ESR1, DES, and SLC12A2 for whole blood and two tissue-specific genes (ADAMTS5 and PCOLCE2). Enrichment analysis highlighted biological processes involving vagina development, glycosaminoglycan binding, and sulfur compound binding. Phe-MR analysis indicated no significant adverse effects for most genes, except for ESR1 and DES.Conclusion: This study investigates the biological roles of potential drug targets for POP, identifying promising candidates for future research and drug development in POP treatment. Keywords: pelvic organ prolapse, druggable genome, Mendelian randomization, enrichment analysis, drug safety evaluation, phenome-wide association study