L26/P-337 Monocyte and neutrophil morphology as putative causal factors for endometriosis and adenomyosis: a two-sample bidirectional Mendelian randomization study

Abstract Study question Do monocyte and neutrophil morphology traits causally linked to endometriosis and adenomyosis risk? Summary answer Lower monocyte granularity (MO-SSC) and lower neutrophil nucleic acid content (NE-SFL) were associated with higher risks for endometriosis and adenomyosis, respectively. What is known already Endometriosis and adenomyosis involve aberrant inflammatory/immune responses. Observational studies and several Mendelian Randomization (MR) analyses have linked systemic immune dysfunction and specific immune cell subtypes to endometriosis risk. Yet the causal role of specific morphological and functional properties of innate immune cells remains poorly established. High-throughput haematology analyzers quantify morphology/biophysics (e.g., side scatter as granularity; side fluorescence as nucleic-acid content), which may better index innate immune functions. However, whether these traits causally alter gynaecologic disease risk remains unclear. Study design, size, duration A two-sample, bidirectional Mendelian randomization study using summary-level GWAS data in European participants. SNP instruments for 12 non-classical neutrophil and monocyte morphological traits (ncCBC) were obtained from publicly available association results deposited in GEO (GSE119453) and SRA (PRJNA491478), using genome-wide significant, LD-clumped variants. Outcomes were endometriosis (IEGC; GCST90205183) and adenomyosis/endometriosis of uterus (FinnGen: Adenomyosis; N14_endometriosis_uterus). Primary analyses used IVW, with weighted median and MR-Egger sensitivity analyses and FDR correction. Participants/materials, setting, methods Independent genome-wide significant variants (P < 5 × 10−8), with instrument strength ensured (F-statistic>10), were LD-clumped (r²≤0.01; 500 kb) and used as instruments. We conducted 24 primary two-sample MR analyses using inverse-variance weighted (IVW) estimation reported as ORs. Robustness was evaluated using weighted median and MR-Egger methods, alongside heterogeneity and pleiotropy diagnostics (Cochran’s Q; MR-Egger intercept). Multiple testing was controlled using false discovery rate (FDR<0.05). All analyses were conducted in R using TwoSampleMR (v0.5.7). Results were visualized with ggplot2. Main results and the role of chance Across 24 prespecified IVW analyses, two associations showed the strongest evidence. For endometriosis, a 1-SD decrease in monocyte granularity (MO-SSC) was associated with increased risk (IVW β = −0.098 per 1-SD increase; OR per 1-SD decrease≈1.10, 95%CI 1.03–1.18; p = 0.00495; nsnp=31). Heterogeneity was modest (Cochran’s Q p = 0.025). The MR-Egger slope was directionally concordant (p = 0.048) with no evidence of directional pleiotropy (Egger intercept p = 0.519). The MR-PRESSO global test suggested some dispersion (p = 0.0166), but no outlier variants were identified. For adenomyosis, a 1-SD decrease in neutrophil nucleic-acid content (NE-SFL) was associated with increased risk (IVW β = −0.0855; OR per 1-SD decrease≈1.09, 95%CI 1.03–1.15; p = 0.00366; nsnp=56). Heterogeneity was low (Q p = 0.316), the MR-Egger slope was direction-consistent (p = 0.136), and the intercept was null (p = 0.874). Leave-one-out analyses did not indicate single-SNP dependence, and funnel plots were broadly symmetric. After FDR correction across 24 IVW tests, both signals were borderline (q≈0.057), with no additional associations surviving correction. Limitations, reasons for caution The leading associations were borderline after FDR correction and should be considered hypothesis-generating pending independent replication and functional validation. All GWAS datasets were derived from European-ancestry populations, which may limit generalizability to other ancestries and settings. Wider implications of the findings Our findings implicate innate immune-cell functional state (particularly reduced monocyte granularity) as a potential causal contributor to endometriosis susceptibility. If replicated, they support prioritizing monocyte activation/granularity pathways for translational studies and may inform future immune-modulatory prevention or treatment strategies. Trial registration number No