ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2018 Jan 1;103(1):228-234

[Comments on 7.5 and 7.6] Remarkably, the timing of puberty shows important differences between individuals¹. Based on twin studies, differences in pubertal timing are considered to depend on genetic factors which account for up to 60-70% of the variance, while environmental factors also influence pubertal timing. Based on recall of age at menarche, almost 400 genetic loci have been shown to be associated with this late pubertal event, explaining 7.4% of the population variance². The first study reports an enlarged genomic analysis for age at menarche in a very large sample of women using densely imputed genomic data. These findings increase by more than three-fold the number of independently associated signals and bring growing evidence for a significant role of imprinted genes in the regulation of puberty timing. In addition, the reported data support new causal links with susceptibility to sex-steroid-sensitive cancers in women and men. Increasing age at menarche was associated with lower risk for breast, ovarian and endometrial cancer in women, and lower risk of prostate cancer in men.

The vast majority of genome wide studies focus on age at menarche to identify genetic determinants of puberty timing. However, the initial clinical hallmark of female pubertal onset is thelarche. In the second study, a population-based study comprising 1478 healthy Danish girls, the researchers observed a differential impact of genetic variations in FSHR and FSHB on timing of thelarche and menarche. Whereas LIN28B (rs7759938) was associated with both thelarche and menarche, FSHB c.2211G.T and FSHR c.229G.A were associated with age at thelarche, but not with age at menarche. This study is the first to report a differential impact of distinct genetic loci on different female pubertal milestones. It stresses the value of precise endpoint definition in genetic association studies.

1. Parent AS, Franssen D, Fudvoye J, Gérard A, Bourguignon JP. Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents. Front Neuroendocrinol. 2015 Jul;38:12-36.

2. Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014 Oct 2;514(7520):92-97.