We report a large genetic study of puberty timing in males and females. Our findings are the first to quantify the strongly shared genetic basis for puberty timing between sexes, and this is consistent with the largely sex-concordant effects of disruptive mutations in rare disorders of puberty8,9. Accordingly, our findings support the validity of recalled age at voice breaking in men as a marker of puberty timing in epidemiological studies, consistent with the informative prospective assessment of this phenotype2.

Independent signals at seven loci previously identified for age at menarche in women5 (including three independent signals at the LIN28B locus) passed the genome-wide statistical significance threshold for age at voice breaking in men (Table 1). These included the strongest reported common and low-frequency signals for age at menarche at LIN28B and ALMS1, respectively, and other signals with relatively large effects. This observation is consistent with the largely shared genetic architecture for puberty timing between sexes.

The overlapping genetic architecture for puberty timing in men and women provided the rationale for a pooled meta-analysis across the sexes. Notably, we identified two novel signals, near RORB and RXRA, which add to the reported signals near to other retinoic acid receptor-related genes, RORA and RXRG5, and a fifth signal (near RXRB) showed sub-genome-wide significant association with puberty timing. The retinoic acid receptor-related and retinoid X receptors function as transcription factors that dimerize and regulate nuclear receptors to influence cell differentiation, development, circadian rhythm and metabolism13. Their receptor partners include the canonical receptors for oestrogen and androgens among other hormones and metabolites14, and their conformational changes may alter receptor sensitivity15. Collectively these findings strengthen the evidence for an aetiological role of retinoic acid and retinoid receptors in the regulation of puberty timing, although their relative importance to male versus female puberty remains to be established. Further studies are also needed to identify functional links between these allelic signals and specific gene and protein functions.

Three additional novel signals reached genome-wide significance for puberty timing, represented by variants in/near RNF144B-ID4, LEPR and KAL1. All three were associated with puberty timing in both men and women, two of which had stronger effects in males (LEPR and RNF144B-ID4). The signal at 6p22.3 resides in a gene desert with the two nearest genes, ID4 and RNF144B, located 760 kb and 607 kb away, respectively. Notably, it also lies 852 kb from KDM1B, a gene in the same family of histone demethlyases highlighted previously for age at menarche (variants in/near KDM3B, KDM4A and KDM4C represented genome-wide significant signals)5. Variants near KAL1 on Xp22.31 had not been highlighted by previous GWAS of female puberty timing due to paucity of X-chromosome data in those studies. rs5978985 is correlated with a reported signal for circulating free testosterone concentrations in males (r2=0.35 with rs5934505)16 and KAL1 encodes the extracellular matrix glycoprotein anosmin-1 implicated in the embryonic migration of gonadotrophin releasing hormone and olfactory neurons. Deleterious mutations in KAL1 cause X-linked Kallmann syndrome, characterized by hypogonadotropic hypogonadism and anosmia8. rs140410685 near LEPR, which encodes the leptin receptor, is uncorrelated with a reported neighbouring signal for age at menarche (r2∼0 with rs10789181)5, and shows no reported association with adult BMI in reported GWAS meta-analyses (rs2186245 r2=1 proxy, P BMI =0.33, N=233,888)17.

In rare disorders of puberty, disruptive mutations usually have similar effects on puberty timing in both sexes8,9. Notable exceptions are rare mutations in the genes that encode the pituitary hormones, follicle-stimulating hormone and luteinizing hormone, which disrupt puberty in females but not in males18. In normal populations, rapid postnatal weight gain predicts earlier puberty timing in both sexes, but the influence of low birth weight is apparent only in females2. We found that only a small minority of signals showed sex-discordant effects, most notably rs9321659 at the SIM1-MCHR2 locus. SIM1 encodes a transcription factor regulator of hypothalamic paraventricular nucleus development and function. Rare deleterious mutations cause hyperphagia and severe early onset obesity affecting both males and females19; however, rs9321659 is reportedly not associated with adult BMI (P=0.56)17. Overall, these data suggest that combining male and female data genome wide is likely to yield novel shared puberty loci, but care should be taken to assess for potential heterogeneity in the effects.

Finally, our observed genetic correlations indicate the relevance of puberty timing to later life health outcomes in both men and women. Consistent with traditional epidemiological evidence20,21,22, earlier puberty timing was genetically related to higher risks of adverse health-related outcomes, including higher BMI, polycystic ovary syndrome, type 2 diabetes, lipid profiles and cardiovascular disease; it was favourable only for bone mineral density. LD score regression is a powerful tool to identify potential causal relationships between traits; however, limitations include the inability to establish causal directions and to adjust for potential-mediating factors. The relationship between puberty timing and obesity risk is complex, with plausible bi-directional mechanisms. Previous studies have reported that genome-wide significant signals for higher BMI, both in combination and individually, are associated with earlier puberty timing in females5,23,24. Conversely, in the opposite direction, earlier puberty timing associated with the LIN28B rs314276 C-allele leads to faster adolescent weight gain and higher post-pubertal BMI, without effects on pre-pubertal BMI25. Further studies are required to explore whether health outcomes related to earlier puberty timing are fully mediated by higher BMI.

In summary, this large-scale assessment of the genetic architecture of puberty timing in males quantifies the extent of shared aetiology between sexes, extends the evidence implicating retinoic acid-related receptors in the regulation of puberty timing, and supports the relevance of puberty timing in both sexes to the aetiologies of various health-related outcomes.