Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study

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Background: Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity.
Methods and Findings: One-sample Mendelian randomization (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1991-92. Time-sensitive exposures were age at menarche/voice breaking. Outcomes measured at age 18y were body mass index (BMI), dual-energy X-ray absorptiometry-based fat mass index, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance (NMR) spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, two-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, one-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per-year) was associated with -1.38 kg/m2 of BMI at age 18y (or -0.34 SD-units, 95% CI=-0.46, -0.23; P=9.77x10-09). This attenuated 10-fold upon adjustment for BMI at age 8y, to -0.12 kg/m2 (or -0.03 SDs, 95% CI=-0.13, 0.07; P=0.55). Associations with blood pressure were similar but were small and inconsistent across other traits. In negative control MR analyses, later age at menarche was associated with -0.77 kg/m2 of pre-pubertal BMI measured at age 8y (or -0.39 SDs, 95% CI=-0.50, -0.29; P=6.28x10-13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by -0.26y, 95% CI=-0.37, -0.16; P=1.16x10-06); likewise among males and both sexes combined. In two-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with -0.81 kg/m2 of adult BMI (or -0.17 SD units, 95% CI=-0.21, -0.12; P=4.00x10-15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio=0.52 per year later, 95% CI=0.48, 0.57; P=6.64E-15). Study limitations include modest sample sizes for one-sample MR, lack of inference to non-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. Cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors.
Conclusions: Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.
Original languageEnglish
Article numbere1002641
Number of pages25
JournalPLoS Medicine
Issue number8
Publication statusPublished - 28 Aug 2018

Structured keywords

  • ICEP


  • Puberty timing
  • Menarche
  • Body mass index
  • DXA
  • Cardiometabolic traits
  • Mendelian randomization


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