Endocrine Abstracts

Background: The timing of puberty varies widely between individual children. Those in the extreme early or late groups present commonly to endocrine clinics. Furthermore, in population studies the continuum in puberty timing is associated with long-term health outcomes, such as obesity, Type 2 diabetes, sex steroid-sensitive cancers and also with the timing of menopause and reproductive lifespan. This timing is highly heritable. Genome-wide association studies (GWAS), which genotype hundreds of thousands of common genetic variants located across the entire genome, have identified many specific genetic determinants of pubertal timing and these findings have informed the mechanisms that link earlier pubertal timing to increased risks of disease.

Methods & Findings: Through ReproGEN and other large international GWAS consortia, we have identified hundreds of genomic loci with highly robust associations with puberty timing in both sexes, and with menopause timing in women. These studies have shone new light into the biological regulation of the reproductive axis. For puberty timing, many loci implicate genes that regulate the hypothalamo-pituitary-gonadal axis, energy homeostasis and weight gain, and other unanticipated pathways such as genomic imprinting. For menopause timing, DNA damage sensing and repair is the predominant overall mechanism, but there are notable contributions by some hypothalamo-pituitary-gonadal axis genes.

Discussion: This talk will provide an update on GWAS for puberty and menopause timing and will highlight the clinical implications of the findings.