New Genetic Research Links Early Puberty in Girls to Weight Gain

A Cambridge-led study has discovered that genes can indirectly influence the age at which girls experience their first period by accelerating childhood weight gain, a known risk factor for early puberty. Additionally, some genes can directly affect the timing of puberty, with significant impacts.

Published in the journal Nature Genetics, the research identified over 1,000 DNA variants that influence the age of first menstruation, with around 600 of these variants being newly observed.

Girls typically begin puberty and start menstruating between the ages of 10 and 15, though the average age has been decreasing in recent decades. The exact reasons for this remain unclear. Early puberty is associated with a higher risk of several diseases later in life, including type 2 diabetes, cardiovascular disease, and certain cancers. Conversely, later puberty is linked to better health in adulthood and a longer lifespan.

Just under half (45%) of the discovered genetic variants affected puberty indirectly, by increasing weight gain in early childhood.

In the study, researchers from Cambridge’s MRC Metabolic Diseases Unit discovered that a brain receptor known as MC3R detects the body's nutritional state and regulates the timing of puberty and growth rate in children. This finding explained how nutritional status can influence puberty. Additionally, other identified genes appear to act in the brain to control the release of reproductive hormones.

The scientists also examined rare genetic variants that, although carried by very few individuals, can significantly impact puberty timing. For instance, they found that one in 3,800 women carry variants in the gene ZNF483, causing these women to experience puberty on average 1.3 years later. The researchers developed a genetic score predicting the likelihood of a girl experiencing very early or very late puberty.

Girls in the highest 1% of this genetic score were 11 times more likely to have extremely delayed puberty, starting after age 15. Conversely, those in the lowest 1% were 14 times more likely to experience extremely early puberty, beginning before age 10.

“This is the first large-scale analysis of rare genetic variants, identifying six genes that significantly affect puberty timing. Although discovered in girls, these genes often impact boys similarly. The mechanisms we found could lead to interventions for early puberty and obesity. In the future, genetic scores could help predict very early or late puberty. The NHS is already trialling whole genome sequencing at birth, providing the necessary genetic information. Currently, children with early puberty– at age seven or eight – are offered blockers, but there's a need for additional interventions, such as oral medications or behavioural approaches, to support those who don’t meet this threshold, which could be crucial for their long-term health,” said the authors.

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