14th December 2008

Brain Background to Body Mass

Brain genes associated with increased body mass

NEGR1

<em>NEGR1</em> (top panel) is tagged by SNPs in this study: the most significant of these is rs2815752 (bottom panel, arrowed), which lies some 75,000 bp away from the gene. However, rs2815752 also tags a copy-number variant (a 45,000 bp deletion: indicated by pink panel) that includes conserved sequences that could be involved in regulation of <em>NEGR1</em>.

A genetic study of more than 90,000 people has identified six new genetic variants that are associated with increased Body Mass Index (BMI), the most commonly used measure of obesity. Five of the genes are known to be active in the brain, suggesting that many genetic variants implicated in obesity might affect behaviour, rather than the chemical processes of energy or fat metabolism.

Obesity is an increasing problem that results in individual risk to health as well as increasing burdens on health care systems. By identifying genetic variants that affect obesity, researchers hope to understand better the mechanisms regulating energy balance, which will guide the development of new therapies and help to develop improved diagnosis.

The study is published in Nature Genetics by the GIANT Consortium and includes authors from more than 60 institutions.

"It might seem remarkable that it is the brain that is most commonly influenced by genetic variation in obesity, rather than fat tissue or digestive processes," says Dr Inês Barroso, a senior author on the study, from the Wellcome Trust Sanger Institute. "Until 2007, no genetic associations had been found for 'common obesity', but today almost all those we have uncovered are likely to influence brain function."

Increase in weight occurs when calories taken in exceed calories burned, but behind that simple equation lie behavioural processes such as appetite and satiety, as well as the biochemical mechanisms our bodies use to process foods and use stores of energy, such as fat tissue. A part of the brain called the hypothalamus controls many of our basic functions such as body temperature, hunger and fluid balance: it is programmed to maintain the status quo.

" Until 2007, no genetic associations had been found for 'common obesity', but today almost all those we have uncovered are likely to influence brain function "

Dr Inês Barroso

"Very occasionally, mutations in genes active in the hypothalamus have dramatic consequences for weight gain," explains Dr Ruth Loos, a leading author from the Medical Research Council Epidemiology Unit, "such that people carrying these mutations are severely obese. Such mutations might be considered exceptional."

"However, we suggest that the picture for common obesity is very similar: many or most genes associated with increased BMI are active in the brain."

Studies in twins suggest that genetics can account for 40-70% of the variation in BMI. Yet only one of the genes that were previously discovered had been thought to be linked to increased BMI or obesity in humans. The six new candidate genes provide a rich pool of resources to understand some of the processes in the brain that drive increased BMI and common obesity.

They also highlight the role of different types of mutation: intriguingly, one of the variants does not seem to mark a single-base change in the human genome, but rather the loss of a region of DNA of around 45,000 bases. The authors suggest that this lack of genome sequence near a gene called NEGR1might knock out genomic sequences that regulate activity of NEGR1. Such a variant has not been previously detected in studies of common obesity.

"It may seem surprising that we know so little about the biology of such an important medical and social issue," says Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford, a senior author on the paper. "We can use genetics to open the door on some of the processes that contribute to individual differences in the predisposition to obesity. We are finding that common diseases have complex causes, and it is only by understanding the biology that we can start to make rational attempts to treat and prevent conditions such as this."

"Studies such as this are uncovering more and more genetic changes that are involved in more and more diseases. This is a remarkable time for human genetics."

The authors point out that perhaps dozens of similar variants remain to be discovered. The effects of the variants identified in the new study are modest: someone who carries all the risk variants would typically be 1.5-2 kg heavier than an average person. The findings of this study will pave the way for future investigations to uncover more of the elusive variants, perhaps through sequencing of whole genomes, which has become more efficient and cost-effective in the past year or so.

The research also helps to set the stage to unravel the two influences of genetics and environment. Future research could harness the power of longitudinal cohort studies, which track the health of many subjects through time, thereby providing the tools to map gene-environment interactions.

"As we uncover more variants, we will gain a better basic understanding of obesity, which in turn will open doors to previously unimagined areas of clinically relevant research," explains Joel Hirschhorn, Associate Professor of Genetics at Children's Hospital/Harvard Medical School and at the Broad Institute. "We hope that these advances will guide the development of more effective treatments and interventions."

Notes to Editors

Publication details

  • Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

    Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O'Rahilly S, Purmann C, Rees MG, Ridderstråle M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N, Wellcome Trust Case Control Consortium, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, Hirschhorn JN and Genetic Investigation of ANthropometric Traits Consortium

    Nature genetics 2009;41;1;25-34

Funding

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

Support for the Study

The authors are extremely grateful to all of the participants in each of the studies contributing to this effort. Full acknowledgments can be found in Supplementary Information.

Participating Centres

A full list of participating centres is available at the Nature website, which includes the GIANT (Genetic Investigation of ANthropometric Traits) consortium.

Broad Institute

The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease.

The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is jointly governed by the two universities.

Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines.

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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 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.

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The goal of the MRC Epidemiology Unit is to study the genetic, development and environmental determinants of obesity, diabetes and related metabolic disorders and to contribute to the scientific basis of prevention.

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