Age at Menarche and Coronary Artery Disease Risk: Divergent Associations With Different Sources of Variation.

Summary

In 201,037 UK Biobank women with validation in 23,268 WGHS participants, the authors decomposed age at menarche (AAM) into polygenic and non-polygenic components. Earlier genetically predicted AAM showed linear associations with higher CAD risk and risk factors, whereas PGS-adjusted (non-polygenic) AAM showed U-shaped associations. Findings support a causal role for earlier AAM in CAD, while later AAM likely reflects non-causal shared determinants.

Key Findings

• Genetically predicted earlier AAM showed linear associations with higher CAD risk and adverse cardiometabolic profiles.
• PGS-adjusted AAM exhibited U-shaped associations with CAD, HbA1c, triglycerides, HDL-C, and waist-hip ratio.
• Results imply early AAM may be causally linked to CAD, while later AAM reflects shared non-genetic determinants of both delayed menarche and CAD risk.

Clinical Implications

Risk stratification should recognize that early menarche likely confers causal cardiometabolic risk, whereas late menarche may signal underlying dysmetabolism rather than be a causal target; interventions should focus on mediators (glycemia, lipids, adiposity).

Limitations

• Follow-up duration and event adjudication details not specified in abstract.
• Polygenic scores capture common variants; residual confounding from environment and rare variants remains.

Future Directions

Mendelian randomization integrating rare variants and longitudinal mediation analyses to test glycemia, lipids, and adiposity as pathways; inform risk scores that differentiate causal from non-causal signals.