Scientists have identified over 1,000 genetic variants influencing the onset of menstruation, shedding new light on the complex interplay between genetics, weight gain, and puberty timing. This landmark study could pave the way for novel interventions in early puberty and obesity.
In a groundbreaking study published in Nature Genetics [1], researchers have uncovered more than 1,000 genetic variants that influence the age at which girls experience their first menstrual period. This extensive research, led by the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, analysed the DNA of approximately 800,000 women from diverse populations across Europe, North America, Asia, and Korea.
The findings reveal a complex genetic landscape underlying puberty timing, with potential implications for understanding and managing related health risks.
The study identified that nearly half (45%) of the discovered genetic variants affect puberty indirectly by accelerating weight gain in early childhood. This finding underscores the intricate relationship between genetics, body weight, and puberty onset.
Professor John Perry, the corresponding author, explained: “Many of the genes we’ve found influence early puberty by first accelerating weight gain in infants and young children. This can then lead to potentially serious health problems in later life, as having earlier puberty leads to higher rates of overweight and obesity in adulthood.”
Previous research by the team, in collaboration with Cambridge’s MRC Metabolic Diseases Unit, had already identified a brain receptor called MC3R that detects the body’s nutritional state and regulates puberty timing and growth rate in children. This mechanism provides insight into how genetic factors can influence puberty through weight gain.
Rare genetic variants with significant effects
In addition to common genetic variants, the researchers analysed rare variants carried by very few individuals but with potentially large effects on puberty timing. One striking example is a variant in the ZNF483 gene, carried by one in 3,800 women, which delayed puberty by an average of 1.3 years.
Dr Katherine Kentistou, lead study investigator, highlighted the significance of this finding: “This is the first time we’ve ever been able to analyse rare genetic variants at this scale. We have identified six genes which all profoundly affect the timing of puberty. While these genes were discovered in girls, they often have the same impact on the timing of puberty in boys.”
Predicting puberty onset
The research team developed a genetic score to predict the likelihood of extremely early or late puberty onset. Girls with the highest 1% of this genetic score were 11 times more likely to experience extremely delayed puberty (after age 15), while those with the lowest 1% were 14 times more likely to have extremely early puberty (before age 10).
Clinical implications
Professor Ken Ong, senior author and paediatrician, discussed the potential clinical applications of these findings: “In the future, we may be able to use these genetic scores in the clinic to identify those girls whose puberty will come very early or very late. The NHS is already trialling whole genome sequencing at birth, and this would give us the genetic information we need to make this possible.”
He added: “Children who present in the NHS with very early puberty – at age seven or eight – are offered puberty blockers to delay it. But age of puberty is a continuum, and if they miss this threshold, there’s currently nothing we have to offer. We need other interventions, whether that’s oral medication or a behavioural approach, to help. This could be important for their health when they grow up.”
What the future holds
This research opens up new avenues for understanding the complex interplay between genetics, weight gain and puberty timing. The identified mechanisms could form the basis for developing interventions for individuals at risk of early puberty and obesity.
As the trend towards earlier puberty onset continues, with potential links to increased risks of type 2 diabetes, cardiovascular disease, and certain cancers in later life, this research provides important insights that could inform future preventive strategies and treatments.
Reference:
- Kentistou, K.A., Kaisinger, L.R., Stankovic, S. et al. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01798-4
