̽��ֱ�� of Cambridge - puberty

Largest ever genetic study of age of puberty in girls shows links with weight gain

cjb250 — Mon, 01 Jul 2024 09:00:22 +0000

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

Published on 1 July in Nature Genetics, the researchers found more than 1,000 variants – small changes in DNA – that influence the age of first menstrual period. Around 600 of these variants were observed for the first time.

̽��ֱ��age at which girls hit puberty and start having periods normally occurs between ages 10 to 15, though this has been getting earlier and earlier in recent decades. ̽��ֱ��reasons for this are not fully understood. Early puberty is linked with increased risk of a number of diseases in later life, including type 2 diabetes, cardiovascular disease, and certain cancers. Later puberty on the other hand, has been linked to improved 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.

Corresponding author Professor John Perry 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.”

Previous work by the team – together with researchers at Cambridge’s MRC Metabolic Diseases Unit – showed that 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, providing a mechanism by which this occurs. Other identified genes appeared to be acting in the brain to control the release of reproductive hormones.

̽��ֱ��scientists also analysed rare genetic variants that are carried by very few people, but which can have large effects on puberty. For example, they found that one in 3,800 women carry variants in the gene ZNF483, which caused these women 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. ̽��ֱ��new mechanisms we describe could form the basis of interventions for individuals at risk of early puberty and obesity.”

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

Senior author and paediatrician Professor 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. ̽��ֱ��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.”

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

Reference
Kentistou, KA & Kaisinger, LR, et al. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nat Gen; 1 July 2024; DOI: 10.1038/s41588-024-01798-4

Genes can indirectly influence the age at which girls have their first period by accelerating weight gain in childhood, a known risk factor for early puberty, a Cambridge-led study has found. Other genes can directly affect age of puberty, some with profound effects.

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

John Perry

Halfpoint Images (Getty Images)

Portrait of a young girl writing in her diary

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Scientists discover how our brain uses nutritional state to regulate growth and age at puberty

Anonymous — Wed, 03 Nov 2021 16:00:45 +0000

These findings, published today in the journal Nature, may explain how humans have been growing taller and reaching sexual maturity earlier over the past century. Over the 20th century, average height increased by about 10 cm in the UK, and up to 20 cm in other countries.

While scientists have long suggested that this phenomenon could be related to more reliable access to food for pregnant women and children, until now, precisely how the body senses its state of nutrition and turns that information into growth and sexual maturation had not been understood.

It was already known that signals reach the brain to indicate the body’s nutritional state, such as the hormones leptin, produced in adipose (fat) cells, and insulin, produced in response to increases in blood sugar levels. In a part of the brain called the hypothalamus, these hormones act on a small group of neurons that produce signals called melanocortins.

̽��ֱ��melanocortins act on a variety of receptors, two of which are present in the brain. One of these, the melanocortin 4 receptor (MC4R) has previously been shown to regulate appetite and lack of MC4R results in obesity; however, the MC4R system does not control the effect of nutrition on growth and timing of puberty.

Now, a study, led by researchers from the MRC Metabolic Diseases Unit and the MRC Epidemiology Unit (both part of the Wellcome-MRC Institute of Metabolic Science) at the ̽��ֱ�� of Cambridge, with collaborators from Queen Mary ̽��ֱ�� of London, ̽��ֱ�� of Bristol, ̽��ֱ�� of Michigan and Vanderbilt ̽��ֱ��, has discovered a role for the brain’s other melanocortin receptor, which is known as the melanocortin 3 receptor (MC3R).

They found that in response to nutritional signals the MC3R system controls the release of key hormones regulating growth and sexual maturation.

To show the link in humans, the scientists searched amongst the half a million volunteers in UK Biobank for people with naturally occurring genetic mutations that disrupt the function of the MC3R. They identified a few thousand people who carried various mutations in the gene for MC3R and found these people were on average shorter and went into puberty later than those with no mutation.

For example, they identified 812 women who had the same mutation in one of their two copies of the MC3R gene. This mutation only partly reduced the ability of the receptor to work. Despite this subtle effect, women who carried this were on average 4.7 months older at puberty than those without the mutation.

People with mutations that reduced the function of MC3R were also shorter and had lower amounts of lean tissue, such as muscle, but it had no influence on how much fat they carried.

To confirm these findings in children, they studied almost 6,000 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) and identified six children with mutations in MC3R. ̽��ֱ��six children were shorter and had lower lean mass and weight throughout childhood, showing that this effect starts very early in life.

All the people identified in these studies had a mutation in only one of the two copies of the gene. Finding mutations in both copies of the gene is vanishingly rare, but in another cohort the researchers were able to identify an individual in the Genes and Health study with a very damaging mutation in both copies of the gene. This person was very short and went into puberty after the age of 20.

This same phenomenon linking adequate nutritional body stores to reproductive maturity is seen right across the animal kingdom, so the researchers conducted studies in mice to confirm that the MC3R pathway operates across species. Work in the laboratory of Dr Roger Cone at the ̽��ֱ�� of Michigan, who had previously demonstrated a role for the MC3R in the control of growth and lean mass in mice, showed that while normal mice shut off their reproductive cycle when they underwent a period of food deprivation, mice engineered to lack the MC3R did not. This confirmed that MC3R is a necessary part of how the nutritional state controls sex hormone production.

Professor Sir Stephen O’Rahilly, a senior author on the study and Director of the MRC Metabolic Diseases Unit at the ̽��ֱ�� of Cambridge, said: “This discovery shows how the brain can sense nutrients and interpret this to make subconscious decisions that influence our growth and sexual development. Identifying the pathway in the brain whereby nutrition turns into growth and puberty explains a global phenomenon of increasing height and decreasing age at puberty that has puzzled scientists for a century.

“Our findings have immediate practical implications for the testing of children with serious delays in growth and pubertal development for mutations in the MC3R.

“This research may have wider implications beyond child development and reproductive health. Many chronic diseases are associated with the loss of lean mass, including muscle, with resultant frailty. This responds poorly to simple nutritional supplements such as protein-rich drinks. ̽��ֱ��finding that the activity of the MC3R pathway influences the amount of lean mass carried by a person suggests that future research should investigate if drugs that selectively activate the MC3R might help redirect calories into muscle and other lean tissues with the prospect of improving the physical functional of such patients.”

Professor John Perry, a senior author on the study from the MRC Epidemiology Unit at the ̽��ֱ�� of Cambridge, said: “This is such an exciting time for human genetics. By analysing the genetic sequences of large numbers of research participants, we can now understand fundamental biological processes that have remained elusive until now. By combining these studies with experiments in cellular and animal models, we will continue to uncover new insights and understand the mechanisms behind human growth and metabolic disease.”

̽��ֱ��research was funded by the UK Medical Research Council, Wellcome and the National Institute for Health Research.

Dr Rob Buckle, Chief Science Officer at the Medical Research Council, which was a funder of the research, said: “These findings have the potential to make a significant step forward in future management of disorders of growth and puberty, and improvements in the health of those suffering from frailty caused by chronic conditions. This study shows the value of long-term investment in both large UK population cohorts and multidisciplinary research to discover the underpinning causes of human health and disease.”

Reference
Lam BYH et al. MC3R links nutritional state to childhood growth and the timing of puberty. Nature; 3 Nov 2021

Adapted from a press release by the Medical Research Council

Cambridge scientists have discovered how a receptor in the brain, called MC3R, detects the nutritional state of the body and regulates the timing of puberty and rate of growth in children and increases in lean muscle mass.

This discovery shows how the brain can sense nutrients and interpret this to make subconscious decisions that influence our growth and sexual development

Sir Stephen O’Rahilly

Katie Gerrard

Young girl

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Study identifies hundreds of genes that influence timing of puberty and alter risk of several cancers

cjb250 — Mon, 24 Apr 2017 15:15:26 +0000

̽��ֱ��study, published today in Nature Genetics and led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the ̽��ֱ�� of Cambridge and other scientists in the international ReproGen consortium, also found new genetic evidence linking earlier timing of puberty to higher risk of several cancers known to be sensitive to sex-hormones in later life, including breast, ovary and endometrial cancers in women, and prostate cancer in men. These influences remained after controlling for body weight, which is important as body weight itself influences both the timing of puberty and the risk of some cancers.

Dr John Perry, Senior Investigator Scientist from the MRC Epidemiology Unit and senior author on the paper, says: "Previous studies suggested that the timing of puberty in childhood was associated with risks of disease decades later, but until now it was unclear if those were circumstantial observations, for example secondary to other factors such as body weight.

“Our current study identifies direct causal links between earlier puberty timing itself and increased cancer risk. This link could possibly be explained by higher levels of sex hormones throughout life, but we need to do more work to understand the exact mechanisms involved. We aim to understand these disease links and thereby contribute to the prevention of diseases in later life."

̽��ֱ��timing of puberty varies widely between individuals but tends to run closely within families. Earlier puberty timing may have advantages for some adolescents, for example for boys who engage actively in sports, but it appears to have largely negative effects on later health, such as higher risks of heart disease and some cancers.

By performing detailed assessments of genetic variants across the whole genome in 329,345 women, comprising data from 40 studies in the ReproGen consortium, UK Biobank, and consented 23andMe customers, this study identified 389 independent genetic signals for age at puberty in women. This observation was then confirmed in a further 39,543 women from the deCODE study, Iceland. Many of these genetic associations were also found to influence age at voice breaking, a comparable measure of puberty timing in men.

These findings shed light on the mechanisms that regulate puberty timing. Dr Perry adds: "These newly identified genetic factors explain one quarter of the estimated heritability of puberty timing. Our findings highlight the remarkable biological complexity of puberty timing, with likely thousands of genetic factors, in combination with numerous environmental triggers, acting together to control the timing of this key transition from childhood to adult life.”

Dr Ken Ong, also from the MRC Epidemiology Unit and joint senior author on the paper, says: "One of the more remarkable findings concerns the role of certain types of genes called imprinted genes, which are only active in your body when inherited specifically from one parent but not the other. We identified rare variants in two genes, which both lower the age of puberty when inherited from your father, but have no effect when inherited from your mother. This is intriguing as it suggests that mothers and fathers might benefit differently from puberty occurring at earlier or later ages in their children."

Reference
Felix R. Day, Deborah J. Thompson, Hannes Helgason et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nature Genetics; 24 April 2017; DOI: 10.1038/ng.3841

̽��ֱ��largest genomic analysis of puberty timing in men and women conducted to date has identified 389 genetic signals associated with puberty timing, four times the number that were previously known.

Our findings highlight the remarkable biological complexity of puberty timing, with likely thousands of genetic factors, in combination with numerous environmental triggers, acting together to control the timing of this key transition from childhood to adult life

John Perry

Jon Bunting

girl in the poppies

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Study identifies gene changes that influence timing of sexual behaviour

cjb250 — Mon, 18 Apr 2016 15:00:54 +0000

Age at first sexual intercourse is known to be influenced by social and family factors, such as peer pressure, but this study shows that genetic factors also have an influence on the timing of this sexual behaviour. It is known from other studies that first sexual intercourse at an early age is associated with adverse educational achievements, physical health and mental wellbeing.

To identify the gene differences which influence timing of sexual behavioural, the researchers at the Medical Research Council (MRC) Epidemiology Unit at the ̽��ֱ�� of Cambridge analysed the genetic data of 59,357 men and 66,310 women aged between 40 and 69 years old part of UK Biobank, a national study for health research.

This analysis identified 38 gene variants that were associated with age at first sexual intercourse. Several of these gene variants were located in or near genes previously implicated in brain development and neural connections, and their analysis uncovered associations with a range of reproductive behaviours, such as age at first birth and number of children.

Dr John Perry, a senior investigator scientist at the MRC Epidemiology Unit, and a lead author of the paper, said: “While social and cultural factors are clearly relevant, we show that age at first sexual intercourse is also influenced by genes which act on the timing of childhood physical maturity and by genes which contribute to our natural differences in personality types.

“One example is a genetic variant in CADM2, a gene that controls brain cell connections and brain activity, which we found was associated with a greater likelihood of having a risk-taking personality, and with an earlier age at first sexual intercourse and higher lifetime number of children.”

In previous studies by the same team, it was found that an earlier age at puberty is linked to increased long-term risks for diseases such as diabetes, heart disease and some cancers.

Dr Ken Ong, a paediatrician and programme leader at the MRC Epidemiology Unit, and a lead author on the paper, added: “We have already shown that early puberty and rapid childhood growth adversely affect disease risks in later life, but we have now shown that the same factors can have a negative effect at a much younger age, including earlier sexual intercourse and poorer education attainment.”

̽��ֱ��team hope that taking account of the timing of puberty and personality type could lead to more targeted and effective approaches to health interventions and promotion of healthy behaviours.

̽��ֱ��research was funded by the MRC.

Reference
Day, FR et al. Physical and neuro-behavioural determinants of reproductive onset and success. Nat Gen; 18 April 2016; DOI 10.1038/ng.3551

Adapted from a press release from the MRC.

A study of over 380,000 people, published today in the journal Nature Genetics, has identified gene differences that influence the age of puberty, sexual intercourse and first birth.

While social and cultural factors are clearly relevant, we show that age at first sexual intercourse is also influenced by genes

John Perry

Amanda Slater

Cherries

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Opinion: Losing your virginity: how we discovered that genes could play a part

Anonymous — Fri, 15 Apr 2016 08:13:05 +0000

As far as big life decisions go, choosing when to lose your virginity or the best time start a family are probably right up there for most people. It may seem that such decisions are mostly driven by social factors, such as whether you’ve met the right partner, social pressure or even your financial situation. But scientists are increasingly realising that such sexual milestones are also influenced by our genes.

In a new study of more than 125,000 people, published in Nature Genetics, we identified gene variants that affect when we start puberty, lose our virginity and have our first child. This is hugely important as the timing of these events affect educational achievements as well as physical and mental health.

Children can start puberty at any time between eight and 14-years-old. Yet it is only in recent years that we have begun to understand the biological reasons for this. Through studies of both animals and humans, we now know that there’s a complex molecular machinery in the brain that silences puberty hormones until the right time. At this point, chemical messengers secreted from the brain begin a cascade of events, leading to the production of sex hormones and reproductive maturity.

Human genetics studies have identified many genes that are linked to individual differences in the onset of puberty. There are broadly two approaches used to map such genes – studies of patients affected by rare disorders that affect puberty and large-scale population studies. ̽��ֱ��former is helpful because it can investigate gene variants that cause extremely early or delayed/absent puberty.

In previous research, we used population studies to survey a large number of individuals using questionnaires and then genome-wide association studies to scan these same participants for common genetic differences. We could then assess whether the participants' reported age at puberty was related to particular gene variants. In this way, we have in a number of studies identified more than 100 such variants, each modifying puberty timing by just a few weeks. However, together they contribute substantially.

We now understand that both nature and nurture play a roughly equal role in regulating the timing of puberty. For example, studies have consistently shown that obesity and excessive nutrition in children can cause an early onset of puberty.

Genetic factors

However, we know far less about the biological and genetic factors behind the ages that we first have sexual intercourse or have a first child. This is because previous research has focused more on environmental and family factors than genetics. But the launch of UK Biobank, a study with over half a million participants, has greatly helped to fill this lack of knowledge.

In our new study, we used this data to survey some 125,000 people in the same way as in the puberty studies. We found 38 gene variants associated with the age of first sexual intercourse. ̽��ֱ��genes that we identified fall broadly into two groups. One category is genes with known roles in other aspects of reproductive biology and pubertal development, such as the oestrogen receptors, a group of proteins found on cells in the reproductive tract and also in behaviour control centres of the brain.

If you went through puberty early you are more likely to have many children in life. Tom Adriaenssen/wikimedia, CC BY-SA

̽��ֱ��other group includes genes which play roles in brain development and personality. For example, the gene CADM2, which controls brain activity and also has strong effects on whether we regard ourselves to be risk-takers. We discovered that this gene was also associated with losing your virginity early and having a higher number of children throughout life. Similarly, the gene MSRA, linked to how irritable we are, was also associated with age at first sexual intercourse. Specifically, people who are more irritable typically have a later encounter. However, more research is needed to show exactly how these genes help regulate the timing of the reproductive milestones.

We were also able to quantify that around 25% of the variation in these milestones was due to genetic differences rather than other factors.

Implications for public health

An important reason why we study reproductive ageing is that these milestones impact reproductive outcomes and also broader health risks. Epidemiological studies show that individuals who go through puberty at younger ages have higher risks of many diseases of old age, such as diabetes, heart disease and breast cancer. Similarly, first sexual intercourse at an earlier age is linked to a number of adverse behavioural, educational and health outcomes.

Using a statistical genetics approach called Mendelian Randomisation, a technique that helps clarify the causal relationship between human characteristics, these studies can tell us whether such epidemiological associations are likely to be causal rather than just random associations. We managed to show that early puberty actually contributes to a higher likelihood of risk-taking behaviours, such as sexual intercourse at an earlier age. It was also linked to having children earlier, and having more children throughout life.

These findings, along with previous studies linking early puberty and loss of virginity to social and health risks, back the idea that future public health interventions should aim to help children avoid early puberty, for example by diet and physical activity and avoiding excess weight gain. Our findings predict that this would have benefits both on improving adolescent health and educational outcomes and also for future health at older ages.

John Perry, Senior Investigator Scientist, ̽��ֱ�� of Cambridge and Ken Ong, Group Leader of the Development Programme at the MRC Epidemiology Unit, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

John Perry and Ken Ong (MRC Epidemiology Unit) discuss how sexual milestones are influenced by our genes and how this can impact on broader health risks.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Age of puberty in girls influenced by which parent their genes are inherited from

cjb250 — Wed, 23 Jul 2014 17:00:00 +0000

̽��ֱ��findings come from an international study of more than 180,000 women involving scientists from 166 institutions worldwide, including the ̽��ֱ�� of Cambridge. ̽��ֱ��researchers identified 123 genetic variations that were associated with the timing of when girls experienced their first menstrual cycle by analysing the DNA of 182,416 women of European descent from 57 studies. Six of these variants were found to be clustered within imprinted regions of the genome.

Lead author Dr John Perry at the Medical Research Council (MRC) Epidemiology Unit, ̽��ֱ�� of Cambridge says: “Normally, our inherited physical characteristics reflect a roughly average combination of our parents’ genomes, but imprinted genes place unequal weight on the influence of either the mother’s or the father’s genes. Our findings imply that in a family, one parent may more profoundly affect puberty timing in their daughters than the other parent.”

̽��ֱ��activity of imprinted genes differs depending on which parent the gene is inherited from – some genes are only active when inherited from the mother, others are only active when inherited from the father. Both types of imprinted genes were identified as determining puberty timing in girls, indicating a possible biological conflict between the parents over their child’s rate of development. Further evidence for the parental imbalance in inheritance patterns was obtained by analysing the association between these imprinted genes and timing of puberty in a study of over 35,000 women in Iceland, for whom detailed information on their family trees were available.

This is the first time that it has been shown that imprinted genes can control rate of development after birth.

Dr Perry says: “We knew that some imprinted genes control antenatal growth and development – but there is increasing interest in the possibility that imprinted genes may also control childhood maturation and later life outcomes, including disease risks.”

Senior author and paediatrician Dr Ken Ong at the MRC Epidemiology Unit says: “There is a remarkably wide diversity in puberty timing – some girls start at age 8 and others at 13. While lifestyle factors such as nutrition and physical activity do play a role, our findings reveal a wide and complex network of genetic factors. We are studying these factors to understand how early puberty in girls is linked to higher risks of developing diabetes, heart disease and breast cancer in later life – and to hopefully one day break this link.”

Dr Anna Murray, a co-author from the ̽��ֱ�� of Exeter Medical School, adds: “We found that there are hundreds of genes involved in puberty timing, including 29 involved in the production and functioning of hormones, which has increased our knowledge of the biological processes that are involved, in both girls and boys.”

̽��ֱ��study was supported in the UK by the Medical Research Council and the Wellcome Trust.

̽��ֱ��age at which girls reach sexual maturity is influenced by ‘imprinted’ genes, a small sub-set of genes whose activity differs depending on which parent passes on that gene, according to new research published today in the journal Nature.

In a family, one parent may more profoundly affect puberty timing in their daughters than the other parent

John Perry

Mario Orellana

Race to puberty (cropped)

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