Potential Causal Association between Plasma Metabolites, Immunophenotypes, and Female Reproductive Disorders: A Two-Sample Mendelian Randomization Analysis

While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished. Instrumental variables for 486 circulating metabolites ( = 7824) and 731 immunophenotypes ( = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis. High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85-12.73], = 2.55 × 10 ). A genetically predicted elevation in the relative count of circulating CD28 CD25 CD8 T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14-1.40], = 1.07 × 10 ), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82-0.93], = 5.94 × 10 ). These results remained consistent in sensitivity analyses. Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.