One-carbon metabolism and risk of PCOS: insights from Mendelian randomization

Abnormal one-carbon metabolism has been reported by observational studies to contribute to an increased risk of polycystic ovary syndrome (PCOS) and undesirable reproductive outcomes in women with PCOS. However, the underlying causal associations remain uninvestigated. This study aims to assess the independent causal links between essential substrates, enzymes and cofactors involved in one-carbon metabolism and PCOS, using bidirectional two-sample Mendelian randomization (MR) and Multivariable MR.

Genetically predicted high levels of folate (OR = 2.92; 95% CI, 1.81 - 3.98; P = 8.32 × 10^- 4), DHFR (OR = 1.25; 95% CI, 1.11-1.41; P = 1.68 × 10^- 4) were causally related to an increased risk of PCOS. Increasing individuals' long-term exposure to circulating vitamin B₆ would mitigate their risk of developing PCOS (OR = 0.56; 95% CI, 0.34 - 0.91; P = 6.34 × 10^- 3). Additionally, suffering from PCOS was revealed to possibly contribute to vitamin B₁₂ deficiency (OR = 0.99; 95% CI, 0.98-1.00; P = 3.61 × 10^-2).

This study integrates metabolomics and genomics to evaluate the causal effects of genetically determined one-carbon metabolism-related factors on PCOS risk, highlighting the critical role of one-carbon metabolism in maintaining reproductive health. These findings underscore the potential of targeting one-carbon metabolism for the prevention and management of PCOS, offering new avenues for clinical interventions.

not applicable.