Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ~370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of the estimated heritability. We implicate ~250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…These results indicate that leptin's effects on metabolism, on growth, and on reproduction engage distinct molecular pathways. Comprehensive genomic analyses in humans have identified PI3K as one of the pathways associated with age at menarche (61). Our findings strengthen these findings and show that PI3K signaling in LR cells is a crucial component of pubertal maturation and reproductive function in adult life.…”

The Genetic Basis of Delayed Puberty

“…Many of these signals have concordant effects on the age at voice breaking, a corresponding milestone in males. However, in women the signals identified had stronger effects on early than on late age at menarche, but in contrast had larger effect estimates for relatively late than relatively early voice breaking in males [18].…”

“…The most recent study of this type comprises 1000 Genomes Project-imputed genotype data from up to ∼370,000 women, and identifies 389 independent signals (p < 5 × 10 -8 ) for age at menarche [18]. The per-allele effect sizes ranged from 1 week to 5 months.…”

“…Humans and mice lacking leptin (Lep ob/ob) or the leptin receptor (LepR db/db) fail to complete puberty and are infertile [68]. Genome-wide association studies of pubertal timing found, in addition to leptin signalling, overlap with several genes implicated in body mass index, including FTO, SEC16B, TMEM18, and NEGR1 [18]. However, whilst self-limited DP in boys is associated with hypoleptinaemia [69], there have been no identified associations of specific leptin or leptin receptor polymorphisms with DP [70].…”

Father Absence and Accelerated Reproductive Development in Non-Hispanic White Women in the United States

“…They correlate millions of genetic variants, called single-nucleotide polymorphisms (SNPs), with phenotypes in samples of tens or even hundreds of thousands of individuals. GWAS on age at menarche (Day et al 2017; Day et al 2015; Perry et al 2014) and age at first birth (Barban et al 2016) provide an opportunity to conduct a molecular test of the rGE hypothesis advanced to explain associations between father absence and timing of puberty. GWAS results can be used to parameterize predictive algorithms, called polygenic scores , which can be applied to genomic data from independent samples (Belsky and Israel 2014; Dudbridge 2013).…”