4th May 2008

Second Genetic Link to Weight and Obesity

New DNA variants found that can help to pile on the pounds

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A study of 90,000 people has uncovered new genetic variants that influence fat mass, weight and risk of obesity. The variants act in addition to the recently described variants of the FTO gene: on average, adults carrying variants in both genes are 3.8 kg (or 8.5 lb) heavier.

The researchers say that their work reinforces the view that not all people will find it equally easy to control their weight, and that these differences are in part genetic.

The research was a massive undertaking that uncovered genetic variants near a gene called MC4R.

"By working together with many international groups we have been able to assemble a sample collection which was large enough to allow this finding to be made," explains Dr Ruth Loos, leading author from the Medical Research Council Epidemiology Unit. "It is only through this collaboration that we have been able to uncover common variants in MC4R that affect many people."

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The study, published in Nature Genetics, is led by investigators from the Cambridge GEM consortium (Genetics of Energy Metabolism) and Oxford University and other institutions from the UK, USA, France, Germany, Italy, Finland and Sweden.

In a study of more than 77,000 adults, the team found that two copies of genetic variants in MC4R resulted in an average increase in weight of about 1.5 kg. Many of the same team showed in 2007 that genetic variants of a gene called FTO could lead to a weight gain of 2-3 kg.

Importantly, the effects of the new gene add to those of FTO: on average, people with both FTO and new MC4R variants are 3.8 kg (8.5 lb) heavier.

"We don't yet understand precisely how these genetic variants cause this weight gain," explains Dr Inês Barroso, Investigator at the Wellcome Trust Sanger Institute and one of the senior authors on the study, "but we can now start to get a grip on the way they work. This is where this research will make a difference."

The MC4R protein can be disrupted in rare, inherited, severe forms of obesity. The team propose that the novel and more common variants alter levels of MC4R protein, reducing its ability to carry out its important roles, which include orchestrating information from the body to control appetite and energy expenditure to keep body weight in balance.

" We can now start to get a grip on the way these genetic variants work This is where this research will make a difference. "

Dr Inês Barroso

"Through this new and powerful genetic approach we are increasingly finding that the genes known to play a role in severe - but rare - diseases are also implicated in much more common disease," explains Professor Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford, UK. "The common variants we are uncovering do not have such a dramatic effect on the normal functioning of the gene as do the rare mutations in MC4R that can cause rare examples of very serious, early onset obesity."

Dramatically, in a study of almost 6000 children, they found that the effects were almost double those seen in adults. Between the ages of four and seven, this additional increase in weight was the result, almost exclusively, of gain of fat tissue, and not due to gain in muscle or other solid tissues.

"Our work to understand common disease, such as obesity, depends on the participation of thousands of people - members of the public who provide samples," explains Professor Nick Wareham, Director of the MRC Epidemiology Unit. "Without their willing participation, we could never achieve the power in our research to make striking findings like this."

"For each discovery, our efforts and the contribution of the participants will lead to improved healthcare for the population at large."

The team emphasize that, although gene variants can affect weight, body mass index and obesity, they are only part of the story: lifestyle actions such as good diet and regular exercise are vital to control of weight.

Notes to Editors

Publication details

  • Common variants near MC4R are associated with fat mass, weight and risk of obesity.

    Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, KORA, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L, Nurses' Health Study, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK, Diabetes Genetics Initiative, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M, SardiNIA Study, Vogel CI, Wallace C, Waterworth DM, Weedon MN, Wellcome Trust Case Control Consortium, Willer CJ, FUSION, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M and Mohlke KL

    Nature genetics 2008;40;6;768-75

Participating groups

A full list of participating groups can be found at the Nature website.

The Cambridge Genetics of Energy Metabolism (GEM) consortium

The Cambridge Genetics of Energy Metabolism (GEM) consortium includes researchers from the Wellcome Trust Sanger Institute, MRC Epidemiology Unit and University of Cambridge Department of Clinical Biochemistry and brings together teams with diverse skills to tackle the task of understanding the genetics of both common polygenic forms and also rare monogenic forms of diabetes and obesity.

Funding

This research programme was supported by the Medical Research Council, the Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, the European Commission, the Academy of Finland, the British Heart Foundation, the National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline, and the German National Genome Research Net.

Additional support was provided to individuals by the US National Institute of Diabetes and Digestive and Kidney Diseases, the Throne-Holst Foundation, the Vandervell Foundation, American Diabetes Association, Unilever Corporate Research and the British Heart foundation.

Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe and Oxford is ranked third in the world for biomedicine. The Medical Sciences Division represents almost one third of Oxford University's income and expenditure and two thirds of Oxford University's external research income. Work ranges from basic science including leading molecular research to studies in humans, with vaccines in field trials for HIV, TB and malaria.

The Medical Research Council supports the best scientific research to improve human health. Its work ranges from molecular level science to public health medicine and has led to pioneering discoveries in our understanding of the human body and the diseases which affect us all.

GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

GlaxoSmithKline sponsored, in part, the CoLaus Study in Lausanne, Switzerland. This study is one of a large panel of academic-industry collaborations that GlaxoSmithKline has set up to decipher the genetic basis of common diseases. Scientists from GlaxoSmithKline and from Lausanne University Hospital collaborated closely with the MRC and Sanger scientists and were involved in the collection and the analysis of the data which led to the present publication.

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The Wellcome Trust Sanger Institute

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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The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

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