Timing of Pubertal Development and Midlife Blood Pressure in Men and Women: A Mendelian Randomization Study

Introduction: Observational studies suggest earlier puberty is associated with higher adulthood blood pressure (BP), but these findings have not been replicated using Mendelian randomization (MR). We examined this question sex-specifically using larger genome-wide association studies (GWAS) with more extensive measures of pubertal timing. Methods: We obtained genetic instruments proxying pubertal maturation (age at menarche [AAM] or voice breaking [AVB]) from the largest published GWAS. We applied them to summary sex-specific genetic associations with systolic and diastolic BP z-scores, and self-reported hypertension in women (nâ =â 194 174) and men (nâ =â 167 020) from the UK Biobank, using inverse-variance weighted meta-Analysis. We conducted sensitivity analyses using other MR methods, including multivariable MR adjusted for childhood obesity proxied by body mass index (BMI). We used late pubertal growth as a validation outcome. Results: AAM (beta per 1-year laterâ =â -0.030 [95% confidence interval,-0.055 to-0.005] and AVB (beta-0.058 [95% CI,-0.100 to-0.015]) were inversely associated with systolic BP independent of childhood BMI, as were diastolic BP (-0.035 [95% CI,-0.060 to-0.009] for AAM and-0.046 [95% CI,-0.089 to-0.004] for AVB) and self-reported hypertension (odds ratio 0.89 [95% CI, 0.84-0.95] for AAM and 0.87 [95% CI, 0.79-0.96] for AVB). AAM and AVB were positively associated with late pubertal growth, as expected. The results were robust to sensitivity analysis using other MR methods. Conclusion: Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.