The international study led by researchers from the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, studied the DNA of close to 800,000 women from Europe, North America, China, Japan, and Korea. The team found more than 1,000 variants (small changes in DNA) that influence the age of menarche, and around 600 of these variants were observed for the first time. 45% of the discovered genetic variants affected puberty indirectly by increasing weight gain in early childhood, according to the researchers.
Weight gain and early puberty
Historically, the age at which girls begin puberty and begin their menstrual cycle occurs between the ages of 10 to 15 years old. However, this trend has started to begin much earlier in recent years, but the reasons for this are not fully understood. What is known is that early puberty is linked with an increased risk for a variety of diseases later in life such as obesity, type 2 diabetes, cardiovascular disease, and certain cancers. On the other hand, later puberty is linked to improved health in adulthood and a longer lifespan.
“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,” said corresponding author Professor John Perry.
Genetic variants and puberty
Previous research has shown that the brain receptor MC3R detects the nutritional state of the body and regulates the timing of puberty and rate of growth in children, providing a mechanism by which this occurs. Other identified genes appeared to be acting in the brain to control the release of reproductive hormones.
Rare genetic variants carried by very few people that can have large effects on puberty were also examined. For example, they found that 1 in 3,800 women carry variants in the gene ZNF483, which caused these women to experience puberty on average, 1.3 years later.
Genetic scores were also created that could predict whether a girl was more likely to experience very early or very late puberty. Those with the highest 1% in this genetic score were found to be 11 times more likely to have extremely delayed puberty after the age of 15 years old. Those with the lowest 1% in this genetic score were found to be 14 times more likely to have extremely early puberty before the age of 10 years old.
What this means
“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. The new mechanisms we describe could form the basis of interventions for individuals at risk of early puberty and obesity,” said lead study investigator Dr. Katherine Kentistou.
“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,” said Professor Ken Ong, senior author and paediatrician. “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.”
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https://www.nature.com/articles/s41588-024-01798-4
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