10 October 2010

Apple-shaped or pear-shaped, it's partly down to your genes

International team of scientists pins down gene variations associated with body fat distribution and obesity

Plot of effect size versus effect-allele frequency of newly identified and previously identified body mass index variants after stage 1 and stage 2 analysis, including the 10 previously identified BMI loci (blue), the 4 previously identified waist and weight loci (green) and the 18 newly identified BMI loci (blue). The dotted lines represent the minimum effect sizes that could be identified for a given effect-allele frequency with 80% (upper line), 50% (middle line) and 10% (lower line) power.

Plot of effect size versus effect-allele frequency of newly identified and previously identified body mass index variants after stage 1 and stage 2 analysis, including the 10 previously identified BMI loci (blue), the 4 previously identified waist and weight loci (green) and the 18 newly identified BMI loci (blue). The dotted lines represent the minimum effect sizes that could be identified for a given effect-allele frequency with 80% (upper line), 50% (middle line) and 10% (lower line) power.

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A whole set of new genes associated with body fat distribution and obesity have been identified in two major studies by an international team of researchers, including the largest study yet of DNA variation across our genomes involving almost a quarter of million people.

The group has identified 13 new gene regions where variations in DNA sequence can be linked to whether we are apple-shaped or pear-shaped. The majority of these variations have a markedly stronger effect in women than in men.

The scientists, led by researchers at Oxford University and the Medical Research Council (MRC) Epidemiology Unit in Cambridge, have also found 18 new genetic variations associated with increased susceptibility to obesity.

The results, published in Nature Genetics, give greater insight into the biological processes that can lead to obesity and that are involved in determining body fat distribution. The work immediately opens up new avenues of research into the biological basis of obesity, but it is possible that such understanding could in time guide the development of new ways of preventing or treating obesity.

"These large studies focusing on common variants have identified important links between common DNA variants and obesity/fat distribution," says Dr Inês Barroso, from the Wellcome Trust Sanger Institute and a senior author on the papers, "but the next big challenge will be to understand the underlying biological and physiological pathways affected by those variants. In part, this increasing understanding will be helped by the overlap between the findings we have made, based on relatively small effects, in many thousands of samples compared with the results from much less common, severely affected people."

"In this exciting work, we have found possible new links between DNA variation and obesity/fat distribution but the next few years promise to be just as exciting as we embark on studies of rare variants."

Apples and pears

Where we store fat in our bodies can influence our health. More fat around our waists (being apple-shaped) is associated with increased risk of type 2 diabetes and heart disease, even after correction for obesity. In comparison, storing fat in thighs and bums (being pear-shaped) has been suggested in some research to offer some protection against diabetes and high blood pressure.

Our waist-to-hip ratio is a good measure of this difference in body fat distribution, and is known - like predisposition to obesity - to be determined to some extent by the genes we inherit.

There are also clear differences in body shape between men and women, but the body processes that determine these differences are not well understood.

" We have found possible new links between DNA variation and obesity/fat distribution but the next few years promise to be just as exciting as we embark on studies of rare variants. "

Dr Inês Barroso

The researchers completed a large genome-wide search for DNA variations that could be connected to waist-to-hip ratios. They identified 13 new gene regions linked to body fat distribution, and confirmed the one previously known genetic link. They show that these genetic variations affect waist-to-hip ratio distinct from any effect on overall obesity.

Seven of the identified genetic variations have much stronger effects in women than in men, suggesting they may underlie some of the difference in fat distribution between the sexes.

Although the gene regions identified explain only around one per cent of the variation in waist-to-hip ratios in the population, they do point towards specific biological mechanisms that are involved in regulating where the body stores fat. The regions implicate genes involved in regulating cholesterol, triglyceride levels, insulin and insulin resistance.

"By finding genes that have an important role in influencing whether we are apple shaped or pear shaped, and the ways in which that differs between men and women, we hope to home in on the crucial underlying biological processes," says Dr Cecilia Lindgren of the Wellcome Trust Centre for Human Genetics at Oxford University, senior researcher on the waist-to-hip ratio study and who was involved in both papers.

"Understanding biology through finding genes is just a first step in a long journey towards treatment, but it is a vital one. As efforts to tackle obesity through changes in lifestyle or by different treatment options have proved extremely challenging, the potential to alter patterns of fat distribution may offer an alternative for future drug discovery."

Genes and obesity

The second study looked for genes connected to body mass index (BMI). BMI is a measure commonly used to classify adults as being overweight (BMI of 25-29.9) or obese (BMI of 30 or greater). The discovery of 18 new genetic regions has more than doubled the DNA variations reliably linked to BMI to 32.

Some of the new findings indicate the involvement of genes active in the brain that influence our appetite and also genes involved in the control of insulin levels and metabolism.

The study also showed that people who inherit many of the BMI-increasing DNA variants from their parents weigh 7-9 kg more than those who inherit few of these variants; this difference in weight is solely due to the fact that they differ genetically. Despite the large difference between the most susceptible and least susceptible, together the 32 confirmed genetic associations still only explain 1.45% of the variation seen in people's BMIs, suggesting there are many more genetic associations still to be found.

"We have conducted the largest ever genome-wide association study so far, and by including almost 250,000 individuals we have been able to identify 18 new genetic regions associated with obesity," says Dr Ruth Loos of the MRC Epidemiology Unit in Cambridge, senior researcher on the BMI study and who was involved in both studies.

"These two studies are the beginning of new insights into to biology of obesity and body shape, which in turn may lead to more targeted approaches to obesity prevention and potentially to the development of new drugs. But we should not forget that, while the genetic contribution to obesity is substantial, a large part of obesity susceptibility remains down to our lifestyle."

The studies were carried out by the GIANT (Genetic Investigation of Anthropometric Traits) consortium, an international collaboration of more than 400 scientists from 280 research institutions with support from many funding agencies worldwide.

Notes to Editors

Waist-hip ratio paper

The study of waist-hip ratio began by combining data from 32 genome-wide studies included over 77,000 participants of European ancestry. The researchers looked for individual DNA changes at over 2.85 million positions across their genomes that could reliably be linked with body fat distribution. The identified gene regions with the strongest associations were then checked with data from a further 29 studies including over 113,500 separate individuals. This revealed 14 gene regions associated with waist-hip ratio, adding 13 new regions and confirming the one previously known association. Seven of the identified genetic variations have much stronger effects in women than in men, suggesting they may underlie some of the difference in fat-distribution between the sexes.

Body mass index paper

The study of genetic determinants of body mass index combined data from 46 studies involving a total of 123,865 people. The genome-wide scans looked for DNA variations at around 2.8 million positions along the genome that were associated with BMI. The genetic regions with the strongest associations were then looked at in a further data set including almost 126,000 individuals. The combined analysis including almost ¼ million people found 32 genetic regions associated with body mass index, confirming 14 genetic variations known to be linked to obesity susceptibility and adding 18 new ones.

Publication details

  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

    Speliotes EK et al.

    Nature Genetics 2010

  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

    Heid IM et al.

    Nature Genetics 2010

Funding

A full list of funding agencies is available on the Nature Genetics website.

Participating Centres

The studies were carried out by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. A full list of participating centres is available on the Nature Genetics website.

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Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of Oxford University's income and expenditure, and two-thirds of its external research income. Oxford's world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in The Gambia. Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for tuberculosis, malaria and HIV, which are in clinical trials.
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The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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