Proteome-wide Mendelian randomization identifies β-nerve growth factor as a target for endometriosis

Endometriosis is a chronic inflammatory disorder with poorly understood mechanisms. Inflammatory proteins are hypothesized to play a causal role, but evidence remains limited. We performed a 2-sample Mendelian randomization study to assess causal relationships between 91 inflammatory proteins and endometriosis. Genetic instruments were derived from protein quantitative trait loci data (14,824 individuals of European ancestry), and endometriosis data were obtained from the Finnish cohort and UK Biobank. Primary analysis used inverse variance weighting and Wald ratio methods, with validation in independent cohorts. Sensitivity analyses included reverse causality, Bayesian colocalization, and phenotype screening. Beta-nerve growth factor (β-NGF) was significantly associated with endometriosis risk (OR = 2.23; 95% CI: 1.60-3.09; P = 1.75 × 10-6), with strong colocalization evidence (PPH3 + PPH4 = 97.22%). C-X-C motif chemokine 11 and signaling lymphocytic activation molecule showed associations in primary analysis but were not validated. Phenotype screening linked C-X-C motif chemokine 11 and signaling lymphocytic activation molecule to autoimmune, metabolic, and oncological conditions. DrugBank analysis identified 5 potential β-NGF-targeted therapies. This study provides robust evidence for the causal role of β-NGF in endometriosis and identifies potential therapeutic targets. These findings advance our understanding of endometriosis pathogenesis and highlight opportunities for targeted treatment development.