Elevated Neutrophil Count as a Causal Risk Factor for Endometriosis: A Mendelian Randomization Study

Endometriosis is a chronic inflammatory gynecological disorder where immune dysregulation plays a central role in its pathogenesis. While previous observational studies have reported associations between circulating blood cell counts and endometriosis risk, it remains unclear whether these hematological alterations are a causal factor or merely a secondary consequence of the disease itself. This study used a bidirectional two-sample Mendelian randomization (MR) approach to investigate causal relationships between six circulating blood cell counts and endometriosis risk.

We conducted bidirectional two-sample MR analyses using GWAS summary statistics from a meta-analysis of up to 563,946 individuals (blood cell traits) and the FinnGen R12 release (endometriosis: 18,349 cases, 208,924 controls). Genetic instruments included basophil, eosinophil, lymphocyte, monocyte, neutrophil, and total white blood cell counts. The inverse-variance weighted method served as the primary analysis, supported by MR-Egger, weighted median, Cochran's Q test, and leave-one-out analyses.

Forward MR analysis revealed that genetically predicted higher neutrophil count was causally associated with increased endometriosis risk (Odds Ratio [OR] = 1.113, 95% Confidence Interval [CI]: 1.038-1.194, P = 0.003). A similar significant causal effect was also found for total white blood cell count (OR = 1.096, 95% CI: 1.028-1.169, P = 0.005). Both associations remained significant after false discovery rate correction. No significant causal effects were observed for basophil, eosinophil, monocyte, or lymphocyte counts. The reverse MR analysis found no evidence of a causal effect of endometriosis liability on any blood cell trait.

This study provides robust genetic evidence that an elevated neutrophil count is a causal risk factor for endometriosis, establishing systemic innate inflammation as a primary contributor to disease etiology rather than merely a secondary consequence. These findings highlight neutrophil-mediated inflammatory pathways as promising targets for novel therapeutic and preventive strategies in endometriosis.