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

Background: In women, both earlier and later age at menarche (AAM) are associated with increased risk of coronary artery disease (CAD). This study sought to determine if the relationship of AAM with CAD and CAD risk factors differs for different underlying sources of variation in AAM - specifically, variation attributable to common genetic variants as represented by a polygenic score (PGS) vs. variation in AAM adjusted for the PGS. Methods: Primary analyses were conducted on data from 201,037 women in the UK Biobank and validation studies on data from 23,268 women in the Women's Genome Health Study (WGHS). For each individual, a PGS for AAM was calculated, then two variables were estimated from linear regression models: the genetically predicted AAM (the estimated AAM for each woman solely due to the effects of common genetic variants) and the PGS-adjusted AAM (estimated AAM for each woman solely due to factors other than the PGS). Logistic regression and linear splines were then used to study the relationships of these variables with CAD and CAD risk factors. Results: Genetically predicted AAM demonstrated a linear relationship with CAD and linear or roughly linear relationships with CAD risk factors. In contrast, PGS-adjusted AAM demonstrated a U-shaped relationship with CAD and with hemoglobin A1c, triglycerides, HDL-C, and waist-hip ratio. Validation studies using WGHS data produced similar results. Conclusions: These results suggest that later AAM itself does not cause increased risk of CAD; rather, upstream sources of variation other than common genetic variants can cause both later AAM and increased risk of CAD. Dysglycemia, dyslipidemia, and central adiposity are candidate mediators of the association of later AAM with increased risk of CAD.