Causal plasma metabolites for breast cancer risk: a two-sample Mendelian randomization study with colocalization evidence

Background This study aimed to estimate causal effects of 1,400 human plasma metabolites on breast cancer (BC) risk using a two-sample Mendelian randomization (MR) framework. Methods We employed a two-sample Mendelian randomization framework to investigate causal associations between plasma metabolites and BC risk. We applied strict quality control with Bonferroni correction and conducted meta-analyses to verify result robustness. Colocalization analysis assessed shared genetic variants between causal metabolites and BC risk. Phenome-wide MR (PheWAS-MR) systematically evaluated metabolite associations across all FinnGen phenotypes. Results Five genetically determined plasma metabolites were identified as the potential causal biomarkers for BC risk, including 3,5-dichloro-2,6-dihydroxybenzoic acid (odds ratio [OR]: 0.90; 95% confidence interval [CI]: 0.87–0.94; p  < 0.001), carnitine C14 (OR: 0.72; 95% CI: 0.64–0.83; p  < 0.001) and epiandrosterone sulfate (OR: 1.04; 95% CI: 1.01–1.06; p  < 0.001), Glyco-beta-muricholate (OR: 0.95; 95% CI: 0.93–0.97; p  < 0.001), N4-acetylcytidine (OR: 0.93; 95% CI: 0.91–0.96; p  < 0.001). Colocalization analysis indicates Glyco − beta − muricholate and Epiandrosterone sulfate were found strong colocalization evidence with BC risk (PPH4 = 1). Conclusions Genetically determined 3,5-dichloro-2,6-dihydroxybenzoic acid, carnitine C14, glyco-beta-muricholate, and N4-acetylcytidine were associated with reduced BC risk, while epiandrosterone sulfate correlated with increased risk. Glyco-beta-muricholate and epiandrosterone sulfate demonstrated colocalization with BC pathogenesis.