The age at which puberty occurs is a highly variable childhood trait and has been epidemiologically linked to various diseases in adulthood. In the largest genetic study of puberty timing conducted to date, researchers have increased the number of independent genetic variants known to be associated with this developmental milestone by more than threefold. The findings, published in Nature Genetics, now cumulatively explain ∼7.4% of the population variance in age at menarche and ∼25% of the estimated heritability.
The researchers, led by John Perry and Ken Ong, analysed data from more than 40 studies encompassing ∼370,000 genotyped and phenotyped women, using age at menarche as a proxy measure of puberty timing. The team identified 389 genetic variants, implicating >200 genes through linked expression changes or non-synonymous coding variation. Identified variants were highly expressed in neural tissues (including the pituitary gland) and overlapped with genes involved in rare pubertal disorders. Notably, low-frequency alleles of the imprinted genes MKRN3 and DLK1 had large effect sizes (delaying puberty timing by 6–9 months) when paternally inherited. Finally, using the identified loci as a proxy for puberty timing (a Mendelian randomization approach), the team demonstrated a causal effect (independent of BMI; a known confounder) of earlier puberty timing on increased risk of sex-steroid-sensitive cancers such as breast and endometrial cancer.
“Although deciphering the biological mystery of puberty timing is interesting in itself, we really want to understand the broader impact of puberty timing on the risk of diseases later in life,” explains Perry. “Other causal disease links beyond cancer probably exist, and understanding these associations could lead to interventions to avoid early puberty timing and its later-life consequences.”
Day, F. R. 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. http://dx.doi.org/10.1038/ng.3841 (2017)
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Scientific Reports (2021)