Genetic Regulation of Puberty Timing in Humans

Abstract

Understanding the regulation of puberty timing has relevance to developmental and human biology and to the pathogenesis of various diseases. Recent large-scale genome-wide association studies on puberty timing and adult height, body mass index (BMI) and central body shape provide evidence for shared biological mechanisms that regulate these traits. There is a substantial genetic overlap between age at menarche in women and BMI, with almost invariable directional consistency with the epidemiological associations between earlier menarche and higher BMI. By contrast, the genetic loci identified for age at menarche are largely distinct from those identified for central body shape, while alleles that confer earlier menarche can be associated with taller or shorter adult height. The findings of population-based studies on age at menarche show increasing relevance for other studies of rare monogenic disorders and enrich our understanding of the mechanisms that regulate the timing of puberty and reproductive function.

Figure 1

Schematic diagram of the biology of puberty initiation, knowledge from rare and monogenetic studies is bounded in red, the suggested mechanisms of common variants are bounded in green.

Figure 2

Plot of the 97 common variants identified by genome-wide association studies for BMI, indicating their per-allele effect sizes on adult BMI (with 95% confidence intervals) compared to their effect sizes on age at menarche. The R² value indicates the strength of correlation between effect sizes. In general, BMI-increasing alleles also confer earlier menarche. The MC4R-region variant (highlighted in red) is a notable exception.

Figure 3

Heatmap indicating the effects of 123 common variants identified for age at menarche on a number of metabolic-related phenotypes (data derived from publically-available datasets,,–78). Green bars indicate menarche age-decreasing variants that are also associated with higher values of other phenotypes; blue indicates menarche age-decreasing variants also associated with lower values of other phenotypes.