ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This multi-ancestry genetic analysis including ~800,000 women, identified 1,080 signals for age at menarche, explaining 11% of trait variance.

Age at menarche is a highly polygenic trait which varies widely among individuals (4-5 years)¹. Recent genome wide association studies, mostly conducted in subjects of European ancestry, have identified several hundred of loci corresponding to ~ 25% of the hereditability^2-5.

The current study expanded the analysis to 799,845 women, including 166,890 of East Asian ancestry. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively, suggesting that common genetic variants contribute to the risk of rare clinical disorders of extremely early and delayed puberty.

Additionally, authors performed an exome-wide association study on 222,283 European-ancestry women and identified several rare loss-of function variants including TACR3 and MKRN3, two genes previously reported in rare monogenic disorders of puberty. This data shows the lower penetrance of rare deleterious variants in population-based studies compared to patient cohorts.

The researchers clustered the 1,080 age-at menarche signals in the Norwegian Mother, Father and Child Cohort Study ( n =26,681 children) by their associations with body weight from birth to age 8 years. This approach provided a clear distinction between age at menarche signals that have direct effects on puberty timing or indirect effects by altering early weight gain.

Using GnRH neuron RNAsequencing, authors identified an enrichment for age at menarche associations among genes that are upregulated when GnRH neurons complete their migration and start to make synaptic contacts. The study also highlighted the crucial role of brain G-protein coupled receptors in age at menarche. Twenty-four of 161 brain-expressed GPCRs were implicated in age at menarche. Functional studies identified physical and functional interactions between MCR3 and GPR83, indicating that increased MC3R function through enhanced GPR83 expression leads to earlier puberty timing.

Some variants were involved in the timing of both menarche and menopause. Interestingly, most variants corresponded to components of the hypothalamic-pituitary-gonadal axes with many of those genes involved in ovarian DNA damage response.

In conclusion, this study doubled the explained variance in age at menarche. Additionally, the authors have developed a common variant polygenic score which will need to be evaluated for determining the risk to develop extreme disorders of puberty timing.

References: 1. Wehkalampi K, Silventoinen K, Kaprio J, Dick DM, Rose RJ, Pulkkinen L, Dunkel L. Genetic and environmental influences on pubertal timing assessed by height growth. Am J Hum Biol. 2008; 20(4):417-23. 2. Day FR, Thompson DJ, Helgason H, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017; 49(6):834-841. 3. Lunetta KL, Day FR, Sulem P, et al. Rare coding variants and X-linked loci associated with age at menarche. Nat Commun. 2015; 6:7756. Erratum in: Nat Commun. 2015; 6:10257. 4. Elks CE, Perry JR, Sulem P, et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat Genet. 2010; 42(12):1077-85. 5. Perry JR, Day F, Elks CE, et al\. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014; 514(7520):92-97.