Genetic factors affect the age of first menstruation in girls by increasing weight in childhood and accelerating puberty

Genes may indirectly influence the age at which girls get their first menstruation by accelerating weight gain in childhood, which is a known risk factor for early puberty, according to a study led by the University of Cambridge. Other genes may directly affect the age of puberty, some with profound effects.

In the largest study of its kind to date, an international team led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge studied the DNA of around 800,000 women from Europe, North America, China, Japan, and Korea.

Published today in the journal Nature Genetics, the researchers found more than 1,000 variants – small changes in DNA – that influence the age of first menstruation. About 600 of these variants were identified for the first time.

The age at which girls enter puberty and begin menstruating typically occurs between the ages of 10 and 15, although this has been happening increasingly earlier in recent decades. The reasons for this are not fully understood. Early puberty is associated with an increased risk of numerous diseases later in life, including type 2 diabetes, cardiovascular diseases, and certain types of cancer. Later puberty, on the other hand, is associated with improved health in adulthood and a longer lifespan.

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

Corresponding author Professor John Perry said: “Many of the genes we found influence early puberty by first accelerating weight gain in infants and young children. This can lead to potentially serious health issues later in life, as early puberty leads to higher rates of overweight and obesity in adulthood.”

Previous work by the team – in collaboration with researchers from the MRC Metabolic Diseases Unit at Cambridge – showed that a brain receptor known as MC3R detects the body’s nutritional status and regulates the timing of puberty and growth rate in children, providing a mechanism by which this occurs. Other identified genes appeared to act in the brain to control the release of reproductive hormones.

Scientists also analyzed rare genetic variants carried by very few people, but which can have significant effects on puberty. For example, they found that one in 3,800 women carries variants of the ZNF483 gene, which caused these women to experience puberty on average 1.3 years later.

Lead researcher Dr. Katherine Kentistou added: “This is the first time we have ever been able to analyze rare genetic variants on this scale. We identified six genes that all profoundly affect the timing of puberty. Although these genes were identified in girls, they often have the same impact on the timing of puberty in boys. The new mechanisms we describe could form the basis for interventions for those at risk of early puberty and obesity.”

The researchers also generated a genetic score that predicted whether a girl is likely to enter puberty very early or very late. Girls in the highest 1% of this genetic score were 11 times more likely to have extremely delayed puberty – after the age of 15. On the other hand, girls in the lowest 1% of the genetic score were 14 times more likely to have extremely early puberty – before the age of 10.

Lead author and pediatrician Professor Ken Ong said: “In the future, we could use these genetic scores in clinics to identify those girls whose puberty will come very early or very late. The NHS is already conducting a trial of whole genome sequencing at birth, which would provide us with the genetic information needed for this.

“Children who present to the NHS with very early puberty – at the age of seven or eight – are offered puberty blockers to delay it. But the age of puberty is a continuum, and if they miss this threshold, we currently have nothing to offer. We need other interventions, whether it is oral therapy or a behavioral approach, to help. This could be important for their health as they grow up.”

Source: University of Cambridge