Genetic analysis of large-scale GWAS data identifies 8 genome-wide significant shared loci between endometriosis and iron homeostasis, with reduced systemic iron status — reflected by lower ferritin and transferrin saturation — associating with increased endometriosis risk. Using linkage disequilibrium score regression, multi-trait GWAS, and bidirectional Mendelian randomisation across cohorts totalling up to 257,953 individuals for iron biomarkers and 60,674 endometriosis cases against 701,926 controls, the study finds suggestive but inconsistent evidence for causal bidirectional effects.
This finding is significant because it attempts to disentangle a longstanding chicken-and-egg problem in endometriosis research. Clinicians have long observed that women with endometriosis carry lower systemic iron stores, but attributing causality has been complicated by menstrual blood loss and peritoneal iron accumulation from retrograde menstruation — both consequences of the disease itself. A shared genetic architecture suggests the relationship is not purely secondary, potentially implicating iron-sensing pathways like hepcidin regulation in disease initiation or progression. For the estimated 190 million women globally affected by endometriosis, this could eventually inform diagnostic biomarker development or even preventive nutritional strategies — though the inconsistent causal directionality here warrants caution. The methodology is rigorous, leveraging multi-ancestry GWAS, but Mendelian randomisation carries its own assumptions around pleiotropy. Critically, this is a preprint posted on medRxiv and has not yet been peer-reviewed; conclusions should be treated as preliminary until independently validated.