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

Area of Science:

• Genetics
• Endocrinology
• Bone Biology

Background:

• Premature ovarian insufficiency (POI) is linked to reduced bone mineral density (BMD) and increased fracture risk.
• The causal relationship between POI and bone health remains unclear, hindering personalized patient management and understanding of shared biology.

Purpose of the Study:

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

Main Methods:

• Utilized bidirectional two-sample MR with genome-wide association study summary statistics.
• Employed inverse-variance weighted method for primary analyses, supplemented by MR-Egger and weighted median.
• Conducted sensitivity analyses for pleiotropy and heterogeneity, controlling for multiple testing with false discovery rate.

Main Results:

• Forward MR showed no significant causal effect of genetically predicted POI on 29 bone health outcomes.
• Reverse MR indicated that higher genetically predicted heel BMD was associated with lower POI risk (OR=0.792).
• Genetic susceptibility to wrist and pelvic fractures was nominally associated with increased POI risk (OR=1.44 and OR=1.177, respectively).

Conclusions:

• No genetic evidence supports POI causally influencing bone health deterioration; bone loss in POI is likely secondary.
• Exploratory reverse MR suggests inherent bone traits may influence POI risk, offering new perspectives for risk assessment.
• Potential bone-ovary biological links were highlighted, requiring confirmation in future studies.