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

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated 339 with various adult diseases. Using 1000-Genome imputed genotype data in up to ~370,000 340 women, we identify 389 independent signals (P<5×10-8) for age at menarche, a notable 341 milestone in female pubertal development. In Icelandic data from deCODE, these signals 342 explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of the 343 estimated heritability. We implicate ~250 genes via coding variation or associated 344 expression, demonstrating significant enrichment in neural tissues. Rare variants near 345 imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects only when 346 paternally inherited. Mendelian randomization analyses indicate causal inverse associations, 347 independent of BMI, between puberty timing and risks for breast and endometrial cancers in 348 women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the 349 genetic regulation of puberty timing and support causal links with cancer susceptibility.