Integrative Mendelian Randomization and Whole-Blood Transcriptomic Analysis Implicate a Myeloid-Inflammation Axis in Polycystic Ovary Syndrome.

BACKGROUND

Immune dysregulation and low-grade inflammation are central to the pathophysiology of polycystic ovary syndrome (PCOS). However, putative causal relationships inferred from genetic instruments and their consistency with transcriptomic readouts remain underexplored.

METHODS

We conducted two-sample Mendelian randomization (MR) to estimate potential causal relationships between 731 immune immunophenotypes and PCOS. In an independent, small whole-blood transcriptomic dataset (Gene Expression Omnibus [GEO]: GSE54248; PCOS n=4, controls n=4), we applied gene-signature-based deconvolution (xCell and Microenvironment Cell Populations-counter [MCP-counter]) and single-sample pathway scoring to profile myeloid cell composition and IL-6/JAK/STAT3 and tumor necrosis factor-α/nuclear factor κB (TNF-α/NF-κB) pathway activity. Robustness of the MR findings was examined by standard sensitivity analyses.

RESULTS

MR indicated opposite-direction associations for key myeloid traits: higher absolute monocyte count was inversely associated with PCOS risk (odds ratio [OR] per standard deviation [SD] increase 0.52, 95% confidence interval [CI] 0.39-0.69, P=6.21x10-6, false discovery rate [FDR] q=0.002), whereas higher CD33+HLA-DR+ absolute count was positively associated with PCOS (OR per SD 1.61, 95% CI 1.27-2.03, P=6.39x10-5, FDR q=0.024). In the exploratory GSE54248 dataset, transcriptomic deconvolution suggested myeloid enrichment in PCOS, with tendencies toward higher signatures of monocytes, macrophages (M1/M2), and myeloid dendritic cells (DCs) and higher composite myeloid scores versus controls. Single-sample pathway analyses were consistent with increased IL-6/JAK/STAT3 and TNF-α/NF-κB activities in PCOS, with large effect sizes (Cohen's d=2.27 and 2.16, respectively) but modest P-values (Wilcoxon P=0.057; Benjamini-Hochberg FDR q=0.143 for both pathways).

CONCLUSION

Genetic and transcriptomic evidence jointly support the concept of a myeloid-inflammation axis in PCOS. The inverse MR association for absolute monocyte count alongside positive risk for CD33+HLA-DR+ compartments, together with cross-cohort evidence of myeloid enrichment and inflammatory pathway activation, is compatible with a potential mechanistic link between immune imbalance and PCOS and provides a hypothesis-generating framework for future therapeutic investigation.