Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study

Abstract

Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = -1.31, 95% CI -2.43; -0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.

Keywords: age at menopause; blood pressure; hypertension; mendelian randomization analysis; menopause; systolic blood pressure.

Figure 1

(A) Forest plot of observational estimates for the association between age at natural menopause (continuous) and blood pressure traits; (B) Forest plot of observational estimates for the association between categories of age at natural menopause and hypertension; (C) Forest plot of observational estimates for the association between categories of age at natural menopause and diastolic blood pressure (DBP); (D) Forest plot of observational estimates for the association between categories of age at natural menopause and systolic blood pressure (SBP). A fixed-effects meta-analysis model was used in all cases. Models adjusted for age and glomerular filtration rate, body mass index, total cholesterol, drinking status, education level, smoking status, diabetes, history of cardiovascular diseases, statin use, hormone therapy, and use of antihypertensive medication. Hypertension was defined as a systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg, and/or the use of antihypertensive medication. Early 40–44, intermediate 45–49, normal 50–54, late ≥55.