Genetic Associations Between Premature Ovarian Insufficiency and Bone Health Traits: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND

Premature ovarian insufficiency (POI) is associated with reduced bone mineral density (BMD) and fracture risk, but the causal direction remains unclear. Clarifying this is crucial for individualized patient management and understanding shared biology between bone and ovary.

OBJECTIVE

To investigate the bidirectional genetic causal relationships between POI and bone health using Mendelian randomization (MR).

METHODS

We performed bidirectional two-sample MR using genome-wide association study summary statistics. Primary analyses used the inverse-variance weighted method, with MR-Egger and weighted median as supplements. Sensitivity analyses included tests for pleiotropy and heterogeneity. Multiple testing was controlled using the false discovery rate.

RESULTS

Forward MR found no significant causal effect of genetically predicted POI on 29 bone health outcomes (all FDR P > 0.05). Reverse MR suggested nominally significant associations: higher genetically predicted heel BMD was associated with lower POI risk (OR = 0.792, 95% CI: 0.635-0.988, P = 0.039), while genetic susceptibility to wrist fracture (OR = 1.44, 95% CI: 1.038-1.986, P=0.025) and pelvic fracture (OR=1.177, 95% CI:1.056-1.312, P=0.003) were associated with increased POI risk.

CONCLUSION

This study found no genetic evidence that POI causally influences bone health deterioration, suggesting that clinical bone loss in POI is likely a secondary consequence. Conversely, exploratory reverse MR analysis identified nominal associations suggesting that inherent bone traits may influence POI risk, offering a novel perspective for risk assessment and highlighting potential bone-ovary biological links; these findings require confirmation in future studies.