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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

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Portrait of a young girl writing in her diary

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Rare genetic variants confer largest increase in type 2 diabetes risk seen to date

cjb250 — Wed, 07 Jul 2021 11:10:25 +0000

Type 2 diabetes is thought to be driven in part by inherited genetic factors, but many of these genes are yet unknown. Previous large-scale studies have depended on efficient ‘array genotyping’ methods to measure genetic variations across the whole genome. This approach typically does a good job at capturing the common genetic differences between people, though individually these each confer only small increases in diabetes risk.

Recent technical advances have allowed more comprehensive genetic measurement by reading the complete DNA sequences of over 20,000 genes that code for proteins in humans. Proteins are essential molecules that enable our bodies to function. In particular, this new approach has allowed for the first time a large-scale approach to study the impact of rare genetic variants on several diseases, including type 2 diabetes.

By looking at data from more than 200,000 adults in the UK Biobank study, researchers from the Medical Research Council (MRC) Epidemiology Unit at the ̽��ֱ�� of Cambridge used this approach to identify genetic variants associated with the loss of the Y chromosome. This is a known biomarker of biological ageing that occurs in a small proportion of circulating white blood cells in men and indicates a weakening in the body’s cellular repair systems. This biomarker has been previously linked to age-related diseases such as type 2 diabetes and cancer.

In results published today in Nature Communications, the researchers identified rare variants in the gene GIGYF1 that substantially increase susceptibility to loss of the Y chromosome, and also increase an individual’s risk of developing type 2 diabetes six-fold. In contrast, common variants associated with type 2 diabetes confer much more modest increases in risk, typically much lower than two-fold.

Around 1 in 3,000 individuals carries such a GIGYF1 genetic variant. Their risk of developing type 2 diabetes is around 30%, compared to around 5% in the wider population. In addition, people who carried these variants had other signs of more widespread ageing, including weaker muscle strength and more body fat.

GIGYF1 is thought to control insulin and cell growth factor signalling. ̽��ֱ��researchers say their findings identify this as a potential target for future studies to understand the common links between metabolic and cellular ageing, and to inform future treatments.

Dr John Perry, from the MRC Epidemiology Unit and a senior author on the paper, said: “Reading an individual’s DNA is a powerful way of identifying genetic variants that increase our risk of developing certain diseases. For complex diseases such as type 2 diabetes, many variants play a role, but often only increasing our risk by a tiny amount. This particular variant, while rare, has a big impact on an individual’s risk.”

Professor Nick Wareham, Director of the MRC Epidemiology Unit, added: “Our findings highlight the exciting scientific potential of sequencing the genomes of very large numbers of people. We are confident that this approach will bring a rich new era of informative genetic discoveries that will help us better understand common diseases such as type 2 diabetes. By doing this, we can potentially offer better ways to treat – or even to prevent – the condition.”

Ongoing research will aim to understand how the loss of function variants in GIGYF1 lead to such a substantial increase in the risk of developing type 2 diabetes. Their future research will also examine other links between biomarkers of biological ageing in adults and metabolic disorders.

̽��ֱ��research was funded by the Medical Research Council. UK Biobank is supported by Wellcome, the Medical Research Council, British Heart Foundation, Cancer Research UK, the UK Department of Health, Northwest Regional Development Agency and the Scottish Government.

Reference
Zhao, Y et al. GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health. Nature Communications 2021; 07 Jul 2021; DOI: 10.1038/s41467-021-24504-y

Scientists at the ̽��ֱ�� of Cambridge have identified rare genetic variants – carried by one in 3,000 people – that have a larger impact on the risk of developing type 2 diabetes than any previously identified genetic effect.

For complex diseases such as type 2 diabetes, many variants play a role [in disease risk], but often only increasing our risk by a tiny amount. This particular variant, while rare, has a big impact on an individual’s risk

John Perry

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DNA jigsaw

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Discovery of genetic variants that protect against obesity and type 2 diabetes could lead to new weight loss medicines

cjb250 — Thu, 18 Apr 2019 15:00:18 +0000

Scientists have known for several years that genes can influence a person’s weight. One of the genes that is known to play a key role in regulating weight is MC4R, which codes for the melanocortin 4 receptor. This receptor acts like a switch in the brain to suppress appetite. People who have genetic variants that disrupt this receptor gain weight easily.

Now, in a study published today in the journal Cell, researchers have shown that other genetic variants in the MC4R gene that increase the activity of this brain receptor can protect people from becoming overweight, a finding that could lead to the development of new medicines that ‘copy’ the protective effect of these genetic variants to achieve or maintain weight-loss.

A team led by Professors Sadaf Farooqi and Nick Wareham and Dr Claudia Langenberg at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge looked at the MC4R gene in half a million volunteers from the UK population who have taken part in the UK Biobank study, finding 61 distinct naturally-occurring genetic variants. While some of these genetic variants predisposed people to become obese, other variants provided protection against obesity and some of its major complications, such as type 2 diabetes and heart disease.

To investigate the reasons for this mystery, Professor Farooqi’s team, who previously showed that MC4R works in the brain as a ‘switch’ to tell us to stop eating after a meal, studied the function of these genetic variants in a number of laboratory experiments. They found that MC4R gene variants linked to higher obesity risk stopped the gene from working, whereas variants that offered protection against obesity kept the gene ‘switched on’.

Around six per cent of study participants carried genetic variants that caused the receptor to remain ‘switched on’. People with these variants would eat less, which could explain their lower weight. People with two copies of these particular variants (1 in over 1,000 people) were on average 2.5 kg lighter than people without the variants and had a 50% lower risk of type 2 diabetes and heart disease.

“This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity,” says Professor Farooqi of the ̽��ֱ�� of Cambridge Metabolic Research Laboratories.

̽��ֱ��discovery adds to recent work by the team which showed that some slim people have a genetic advantage when it comes to maintaining their weight.

“It doesn’t mean that we can’t influence our weight by watching what we eat, but it does mean the odds are stacked against some people and in favour of others,” added Professor Farooqi.

When the researchers looked in detail at the genetic variants in laboratory experiments, they found that MC4R can send signals through a pathway – known as the beta-arrestin pathway – that had not previously been linked to weight regulation. Genetic variants that sent signals preferentially through this pathway were the ones driving the association with protection against obesity and its complications and, importantly, were also associated with lower blood pressure. Designing drugs that mimic the effect of the protective variants in MC4R could provide new, safer weight loss therapies.

“A powerful emerging concept is that genetic variants that protect against disease can be used as models for the development of medicines that are more effective and safer,” said Dr Luca Lotta, Senior Clinical Investigator at the Medical Research Council Epidemiology Unit and joint lead author of the study. “Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.”

“Our work would not have been possible without the unique blend of expertise in large-scale genetic epidemiology analysis and laboratory experiments at the Institute of Metabolic Science,” says Professor Wareham, Director of the MRC Epidemiology Unit and Co-Director of the Institute.

“Genetic studies of thousands of people and a functional understanding of the mechanisms behind protective genetic variants can really help us inform the development of a new generation of medicines for common diseases like obesity and diabetes that affect millions of people globally.”

̽��ֱ��work was funded by the MRC and Wellcome, with support from the NIHR Cambridge Biomedical Research Centre.

Reference
Lotta, LA, Mokrosiński, J et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell; 18 April 2019; DOI: 10.1016/j.cell.2019.03.044

Around four million people in the UK carry genetic variants that protect them from obesity, type 2 diabetes and heart disease, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��team say the discovery could lead to the development of new drugs that help people lose weight.

This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity

Sadaf Farooqi

Siora Photography

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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

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