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 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