ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nature communications vol. 11,1 1536. 24 Mar. 2020. doi: https://www.nature.com/articles/s41467-020-14451-5

This multi-trait genome-wide association study (GWAS) for male puberty timing identifies 76 independent signals for puberty timing and highlights relationships with natural hair colour and lifespan.

The timing of puberty varies widely among individuals and better understanding the genetic basis of such variations and the reasons why earlier puberty is associated with later life diseases is an important challenge. Most of genetic research regarding puberty is based on studies in women. However, despite the overlapping genetic architecture between males and females, a series of genetic signals differ between sexes (1,2).

The authors combined data from two very large GWAS studies (23andMe and UK Biobank), including a total of 205 354 men, and identified new male-specific loci associated with age at voice breaking and thus involved in pubertal timing. Among the new candidates, a non-synonymous variant in ALX4 was identified. ALX4 encodes an homeobox gene involved in fibroblast growth factor signalling whose mutations lead to a male-specific hypogonadism (3). Another missense variant was identified in SRD5A2, which encodes for Steroid 5-alpha-reductase, the disruption of which leads to disorders of sexual differentiation. They also discovered three loci for pubertal timing located proximal to genes known to regulate pigmentation, HERC2, IRF4 and C16orf55, raising suspicion of a phenotypic relationship between inter-individual variation in natural hair colour and puberty timing. Phenotypic and genetic analyses confirmed that susceptibility to darker hair colour also confers earlier puberty timing in a relative sex-specific manner (the association being stronger in men). This suggests the existence of common regulators of melanocortins and gonadotropins or a direct impact of melanocyte signalling on puberty.

Another finding of this study is the genetic association between later puberty timing in males and longer lifespan, in accordance with previous phenotypic studies (4). Underlying mechanisms are still unclear, hypothesis range from a direct causal effect of earlier male puberty timing on earlier mortality to a widespread horizontal pleiotropy where genetic variants influence lifespan through mechanisms separate from puberty timing.

This study demonstrates the utility of a multi-trait large-scale GWAS to better understand the regulation and likely consequences of puberty timing.

References:

1. Day FR, Perry JRB, Ong KK. (2015). Genetic regulation of puberty timing in humans. Neuroendocrinology 102, 247–255.

2. Day FR, Bulik-Sullivan B, Hinds DA, et al. (2015). Shared genetic aetiology of puberty timing between sexes and with health-related outcomes. Nat Commun. 6:8842.

3. Kayserili H, Uz E, Niessen C, et al. (2009). ALX4 dysfunction disrupts craniofacial and epidermal development. Hum Mol Genet. 18(22):4357–4366.

4. Day FR, Elks CE, Murray A, Ong KK, Perry JR. (2015). Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study. Sci Rep. 5:11208.