STUDY QUESTION Is genetic liability to endometriosis associated with iron homeostasis, and is this relationship potentially causal? SUMMARY ANSWER Genetic evidence indicates that reduced systemic iron status is associated with increased risk of endometriosis, with evidence of 8 shared genome-wide significant loci and suggestive but inconsistent evidence for causal bidirectional effects. WHAT IS KNOWN ALREADY Endometriosis is a chronic inflammatory condition associated with local iron accumulation within ectopic lesions and peritoneal cavity, resulting from retrograde menstruation and altered iron homeostasis. Epidemiological studies have suggested that women with endometriosis may exhibit reduced systemic iron stores compared to women without endometriosis, reflected by lower circulating ferritin concentrations, although findings have been inconsistent and may be confounded by menstrual blood loss and inflammation. As observational studies cannot distinguish causal relationships from secondary effects or residual confounding, the potential genetic basis linking iron homeostasis and endometriosis risk remains unclear. STUDY DESIGN, SIZE, DURATION We performed genetic analyses using summary statistics from large-scale genome-wide association studies (GWAS) of endometriosis (overall and stage III/IV disease) and five iron biomarkers (serum iron, ferritin, total iron-binding capacity (TIBC), transferrin saturation, and hepcidin). Analyses included genome-wide genetic correlation using linkage disequilibrium score regression (LDSC), identification of shared genetic variants using multi-trait GWAS (MTAG) and bidirectional Mendelian randomisation to evaluate potential causal relationships. PARTICIPANTS/MATERIALS, SETTING, METHODS Iron biomarker summary statistics came from a six-cohort GWAS meta-analysis (HUNT, MGI, SardiNIA, deCODE, Interval, DBDS; N up to 257,953) of blood-derived serum iron, ferritin, transferrin saturation and TIBC (Moksnes et al., 2022). Endometriosis summary statistics came from a 24-study GWAS meta-analysis (60,674 cases, 701,926 controls; European and East Asian ancestry), 12 of which had surgically confirmed cases (Rahmioglu et al., 2023). Genome-wide genetic correlations between iron biomarkers and endometriosis (overall and stage III/IV disease) were estimated using linkage disequilibrium score regression (LDSC), based on summary statistics aligned to the GRCh37 reference genome and restricted to HapMap3 variants. Multi-trait GWAS (MTAG) was applied to each iron biomarker jointly with endometriosis to enhance discovery of genetic loci. Shared loci were functionally annotated using reproductive and iron related tissues from GTEx v8 and blood from eQTLGen expression quantitative trait loci (eQTL) data. Bidirectional Mendelian randomisation (MR) analyses were performed using genome-wide significant variants across multiple clumping thresholds, with inverse-variance weighting (IVW) as the primary method and sensitivity analyses including weighted median, MR-Egger and MR-PRESSO. MAIN RESULTS AND THE ROLE OF CHANCE Genetic correlation analyses suggested that a genetic predisposition to endometriosis is associated with a profile of lower systemic iron availability. Specifically, genetic liability to endometriosis was associated with higher total iron-binding capacity (TIBC; rg=0.16, p=4x10-4), together with lower transferrin saturation (rg=-0.16, p=0.006) and lower ferritin levels (rg=-0.10, p=0.022), findings that are consistent with reduced iron stores. MTAG identified eight additional genome-wide significant loci for endometriosis and eight loci shared with iron biomarkers, including regions implicating coagulation (F5), reproductive biology (WNT4), and immune and vascular pathways (e.g. ABO, STAT6). Mendelian randomisation analyses provided limited and inconsistent evidence for a causal relationship between iron status and endometriosis. Although the inverse-variance weighted (IVW) model showed nominal associations between higher ferritin levels and a lower risk of endometriosis (OR = 0.85, 95% CI 0.76-0.94; p = 0.002), and between genetic liability to endometriosis and higher TIBC (OR = 1.02, 95% CI 1.01-1.04; p = 0.006), these findings were not consistently supported by sensitivity analyses. MR-PRESSO identified a small number of pleiotropic variants, but their removal did not materially alter the results. LIMITATIONS, REASONS FOR CAUTION Iron biomarker GWAS included males and females, potentially obscuring female-specific effects. Dataset availability restricted analyses to European ancestry, limiting applicability to other populations, and to overall and stage III/IV endometriosis, precluding assessment of other disease subtypes. Heterogeneity across SNP instruments, reflected by Cochran's Q statistics, reduced the precision of Mendelian randomisation estimates. Moreover, the genetic instruments explained only between approximately 1.0% and 18.8% of variance in the iron biomarkers, depending on the clumping threshold, which may have limited power to detect causal effects. WIDER IMPLICATIONS OF THE FINDINGS These findings suggest that endometriosis is genetically associated with reduced systemic iron availability and altered iron homeostasis. Thus, lower systemic iron status observed in women with endometriosis may not be explained solely by menstrual blood loss or dietary factors, but reflect an underlying genetic predisposition. Shared genetic loci implicate coagulation, ABO biology, and immune pathways as potential mechanisms linking iron metabolism and endometriosis. Although Mendelian randomisation did not provide consistent evidence for causality, these findings support a shared genetic architecture and warrant further investigation using female-specific GWAS, refined disease subtypes, and multi-omic approaches. Clinically, these findings suggest that low systemic iron status in women with endometriosis may reflect factors beyond established causes of iron deficiency, including an underlying genetic predisposition.