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Link between weight gain and age of puberty in girls shown in University of Cambridge-led study

Genetic influences on the age of puberty in girls have been revealed in the largest study of its kind to date.

An international team led by researchers at the MRC Epidemiology Unit at the University of Cambridge found that genes can indirectly influence the age at which girls have their first period by accelerating weight gain in childhood.

The average age of puberty in girls has been getting younger
The average age of puberty in girls has been getting younger

Other genes directly affect the age of puberty, some with profound effects, they found.

The researchers studied the DNA of about 800,000 women from Europe, North America, China, Japan and Korea.

More than 1,000 genetic variants - small changes in DNA - were found to influence the age at which girls have their first period, and 600 of these variants were observed for the first time.

Girls normally have their first period between the ages 10 to 15, and the average age has been going down in recent decades for reasons not fully understood.

Early puberty is linked with an increased risk of a number of diseases in later life, including type 2 diabetes, cardiovascular disease and certain cancers.

Later puberty is linked to improved health in adulthood and a longer lifespan.

Nearly half (45 per cent) of the discovered genetic variants affected puberty indirectly by increasing weight gain in early childhood.

Prof John Perry, a corresponding author, said: “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.”

Earlier work by the team, with researchers at Cambridge’s MRC Metabolic Diseases Unit, showed a receptor in the brain known as MC3R detects the nutritional state of the body and regulates the timing of puberty and rate of growth in children.

Other identified genes appeared to be acting in the brain to control the release of reproductive hormones.

The team also analysed rare genetic variants that can have major effects on puberty. One in 3,800 women carry variants in the gene ZNF483 that caused them to experience puberty on average 1.3 years later.

Dr Katherine Kentistou, lead study investigator, added: “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.”

The researchers generated a genetic score that predicted whether a girl was likely to hit puberty very early or very late. Girls in the highest one per cent were 11 times more likely to have extremely delayed puberty – that is, after age 15 years. Girls with the lowest one per cent were 14 times more likely to have extremely early puberty – before age 10.

Senior author and paediatrician Prof Ken Ong said: “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.

“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.”

The research was supported by the Medical Research Council and included data from the UK Biobank.

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