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Plasma Proteome-Wide Mendelian Randomization with Multi-Layer Triangulation Identifies Druggable Targets for Uterine
Xin Wang1, Guanglei Yao1, Wei Ding1
1Department of Urology, The Second People's Hospital of Wuhu, Wuhu, Anhui, People's Republic of China.
Background:
Uterine leiomyoma (fibroids) is the most common benign tumor in women and the leading indication for hysterectomy, yet medical therapy remains limited and largely hormonal. Whether circulating proteins causally influence fibroid risk, and could therefore be repurposed as drug targets, has not been examined proteome-wide.
Methods:
We performed cis-pQTL drug-target MR using plasma protein quantitative trait loci from the UK Biobank Pharma Proteomics Project (Olink; 2923 proteins; n=54,219). Uterine leiomyoma was the outcome in two GWAS: FinnGen R12 (42,107 cases/239,957 controls; discovery) and the European subset of Kim et al 2025 (53,711 cases/380,441 controls; second cohort, partly overlapping). Proteins passing Benjamini-Hochberg correction were prioritized by colocalization (PP4>0.8) in both cohorts across a grid of priors, then triangulated by summary-data-based MR, Steiger filtering, reverse MR, cross-platform SomaScan pQTL, phenome-wide scanning, fibroid-versus-myometrium expression, cross-ancestry look-up and druggability annotation.
Results:
Of 1459 proteins with valid cis instruments, 31 were FDR-significant and six colocalized in both cohorts: ITGA11, RSPO3, EIF2AK3, WNT9A, PARP1 and FSHB. All six were Steiger-correct, strongly instrumented (F 229-769) and free of reverse-causal or cis-pleiotropic signal, and span Wnt, extracellular-matrix, gonadotropin, DNA-repair and integrated-stress-response pathways. Colocalization was prior-dependent: under the most stringent prior only ITGA11 and RSPO3 held in both cohorts, whereas WNT9A and PARP1 did not. FSHB recapitulated approved gonadotropin-axis therapy, an internal positive control. PARP1 colocalized on a second proteomic platform and, with RSPO3, was up-regulated in fibroid vs myometrium. All six were direction-concordant in an independent Asian meta-analysis. Only PARP1 has an approved, direction-matched drug class.
Conclusion:
Colocalized, triangulated plasma proteins implicate Wnt, extracellular-matrix and hormonal pathways in fibroid risk. PARP1 is the most tissue-supported repurposing hypothesis, but its colocalization is prior-sensitive and PARP inhibitors carry oncology-grade toxicity, so it is not a ready therapy for reproductive-age women.
