Causal association of circulating metabolites with female infertility: a bidirectional mendelian randomization analysis.

Abstract

Purpose: The relationship between metabolites and female infertility is unclear. This study employed a bidirectional Mendelian randomization analysis to determine the causal relationship between metabolites and female infertility.

Method: The causal relationship between 1,400 metabolites and female infertility was analyzed using publicly available GWAS data. Significant SNPs were selected as instrumental variables (IVs), with those in linkage disequilibrium (LD) or with an F-statistic below 10 excluded to ensure validity. Independent GWAS datasets for metabolites and infertility were used to avoid sample overlap. The primary method employed was inverse-variance weighted (IVW). Heterogeneity and pleiotropy were assessed, and the results were further validated using single SNP and leave-one-out analyses.

Results: The phosphate to mannose ratio, X-17,654 levels, 1-palmitoleoyl-GPC (16:1) levels, glucose-to-mannose ratio,androstenediol (3alpha, 17alpha) monosulfate (3) levels, 3-methylglutaconate levels, octadecadienedioate (C18:2-DC) levels, bilirubin degradation product, C17H18N2O4 (2) levels, 3-methylglutarylcarnitine (2) levels, eicosenedioate (C20:1-DC) levels, and the phosphate-to-mannose ratio were positively associated with the risk of female infertility. the adenosine 5'-diphosphate (ADP)-to-citrate ratio, 2,2'-methylenebis(6-tert-butyl-p-cresol) levels, sphingomyelin (d18:2/16:0, d18:1/16:1) levels, bilirubin degradation product, C16H18N2O5 (3) levels, and the mannose to trans-4-hydroxyproline ratio were negatively associated with the risk of female infertility. No reverse causal link was identified between metabolites and female infertility.

Conclusion: A significant causal association was identified between 16 specific metabolites and female infertility, with 11 metabolites increasing the risk of infertility, while the other 5 exhibited a protective effect.