Blood metabolites affect spontaneous abortion: a Mendelian randomization study

This study aims to assess the potential relationship between blood metabolites and spontaneous abortion (SA) via Mendelian randomization (MR) analysis. Summary-level metabolite data were downloaded from three large-scale genome-wide association studies (GWAS) involving 147,827 participants with 824 unique blood metabolites. The summary statistics for SA was sourced from European populations involving 9,113 cases and 89,340 controls. In this MR study, potential relationships were primarily determined according to the inverse variance-weighted (IVW) analysis results, which were further verified by other MR analyses. We also conducted several sensitivity analyses to ensure that our results were not influenced by pleiotropy and/or heterogeneity. Additionally, we performed metabolic pathway analysis on significantly SA-related metabolites using the web-based tool MetaboAnalyst 5.0. Eight known metabolites associated with SA were identified. Specifically, four metabolites were positively related to SA: caproate (6:0) (OR = 2.57, 95% CI: 1.18, 5.63), N2, N2-dimethylguanosine (OR = 1.77, 95% CI: 1.16, 2.70), total fatty acids (OR = 1.08, 95% CI: 1.00, 1.17), and ADpSGEGDFXAEGGGVR* (OR = 1.59, 95% CI: 1.08, 2.34). Another four metabolites showed negative associations with SA: succinylcarnitine (OR = 0.53, 95% CI: 0.31, 0.89), citrate (OR = 0.81, 95% CI: 0.70, 0.93), glycerol (OR = 0.84, 95% CI: 0.74, 0.97), and 1-heptadecanoylglycerophosphocholine (OR = 0.32, 95% CI: 0.12, 0.89). Multivariable MR analysis further confirmed a direct effect of caproate (6:0), succinylcarnitine, and N2, N2-dimethylguanosine on SA. Furthermore, we found that the metabolic pathways of glycerolipid metabolism and citrate cycle (TCA cycle) are connected with SA. Our study indicates that blood metabolites have a possible impact on the risk of SA. The identified metabolites and metabolic pathways can be used to explore the mechanisms of SA and potential drug targets.