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

Abstract

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. 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 (n = 194 174) and men (n = 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. AAM (beta per 1-year later = -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. Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.