Metabolic disease group

Type 2 diabetes and obesity are complex disorders whose prevalence has reached epidemic proportions.

In 1985 the number of individuals with type 2 diabetes worldwide was 30 million, the more recent number is more than 150 million, and in the next 20 or so years this disease is expected to double in prevalence to 300 million (See graph below). The increase in the number of subjects with diabetes will not be confined to the Western world and in fact it is expected that most of the rise in prevalence will come from developing countries.

Traditionally thought of as a disease of old age, troublingly it is on the rise in younger age groups. This increase is the result of lifestyle and dietary changes over the last few decades acting on a background of genes that have evolved in an environment where diet and physical activity where very different from today. These changes have led to a rapid rise in the prevalence of obesity which has been paralleled by a rise in diabetes prevalence, for which obesity is a significant risk factor. Because of the complex interaction between environment and genes, identifying genes with a role in the susceptibility to these diseases has been a difficult task. However significant progress has recently been made in the identification of genes with a role in predisposition to type 2 diabetes and obesity.

[Anna Tanczos, Wellcome Images]

Background

Prevalence of Diabetes Worldwide.

Prevalence of Diabetes Worldwide.
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Our aim is to understand the genetic aetiology of type 2 diabetes and obesity. The knowledge of genetic predisposition is important to help those at high risk for these disorders to develop healthier lifestyles and to avoid risky behaviours (such as high fat diets). It can also lead to the development of better drugs that work in each affected individual.

Research

Approach

Approaches taken by the Metabolic Disease Group.

Approaches taken by the Metabolic Disease Group.
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Our studies utilise sequencing of candidate genes in patients with extreme phenotype diseases (morbid childhood obesity, maturity onset diabetes of the young MODY- and syndromes of insulin resistance) to identify rare DNA variants that cause these diseases. Candidate genes are chosen based on knowledge of the disease and of pathways involved in glucose metabolism and feeding behaviour. Extreme phenotypes may be genetically simpler than the more common complex diseases of obesity and type 2 diabetes, facilitating the identification of the underlying genes. Identifying mutations leading to these extreme forms of disease will not only help those affected individuals but provides important information regarding critical pathways with a role in glucose and energy balance. Sequencing of candidate genes also identifies common DNA variants that can be tested for a role in susceptibility to common disease. The effect of these variants on common disease predisposition and on quantitative traits of physiological relevance to obesity and type 2 diabetes is assessed by association studies of large well-characterised populations.

A main focus of our current research involves genome-wide association studies and association studies across regions previously linked to disease, which allow us to use an unbiased approach to study obesity, type 2 diabetes and metabolic quantitative traits. Variants associated with a disease, or quantitative trait, require replication across additional very large population resources to ensure the result is not a false-positive association. Once an association is unequivocal the hard work of fine-mapping the candidate interval and identifying the underlying causal variants begins. Re-sequencing of candidate intervals as well as additional genotyping may be required, as well as the use of additional data such as correlating disease or trait association with expression levels of genes or other large-scale datasets that measure specific traits that may be closer to physiology. Ultimately providing definitive proof of causality remains the most challenging aspect of these projects.

Future

Back to biology is the approach once associations between DNA variants and disease susceptibility have been identified. To further the knowledge from a statistical association to a biologically relevant finding it is imperative to determine the functional implications of those variants in terms of protein structure, activity and action in vivo. To functionally evaluate those genes with genetic and statistical associations with disease will be the next great challenge in complex disease. We have established collaborations with other Sanger Institute researchers and have the ability to study novel genes implicated in disease in model organisms such as zebrafish (collaboration with Derek Stemple's group) and mouse (Sanger Institute Mouse genetics programme). The ultimate aim will be to elucidate how those variants are acting at the cellular and organismal level to increase individual predisposition to disease.

Collaborations

Genetics of Energy Metabolism: A substantial amount of our research is conducted as part of a fully integrated collaborative effort - GEM consortium (Genetics of Energy Metabolism) with the groups of Steve O'Rahilly (Institute of Metabolic Science, Cambridge University) and Nick Wareham (MRC Epidemiology Unit).

Additionally, we engage in collaborative studies with Professor Mark McCarthy (Oxford University), Professor Andrew Hattersley (Peninsula Medical School), Professor Alan Permutt (Washington University in St Louis) and Professor Benjamin Glaser (Hadassah-Hebrew University Medical Center) and are always open to extending our collaborative network in cases where there is mutual scientific benefit.

Diabesity : We are a leading member in the Diabesity project, EU FP6 Integrated Project (LSH-CT2003-503041), a collaboration among 27 partners from 24 European Institutions.

InterAct : We are also key partners in the InterAct project, EU FP6 Integrated Project (LSHM-CT-2006-037197), a collaboration among 36 partners from 30 European Institutions.

Selected Publications

  • Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.

    Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Boström KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjögren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Wellcome Trust Case Control Consortium, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M and Altshuler D

    Nature genetics 2008;40;5;638-45

    PUBMED: 18372903; PMC: 2672416

  • 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

    PUBMED: 18454148; PMC: 2669167

  • The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

    Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S and Schofield CJ

    Science (New York, N.Y.) 2007;318;5855;1469-72

    PUBMED: 17991826; PMC: 2668859

  • Common variants in WFS1 confer risk of type 2 diabetes.

    Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, Lango H, Frayling TM, Neumann RJ, Sherva R, Blech I, Pharoah PD, Palmer CN, Kimber C, Tavendale R, Morris AD, McCarthy MI, Walker M, Hitman G, Glaser B, Permutt MA, Hattersley AT, Wareham NJ and Barroso I

    Nature genetics 2007;39;8;951-3

    PUBMED: 17603484; PMC: 2672152

  • A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.

    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT and McCarthy MI

    Science (New York, N.Y.) 2007;316;5826;889-94

    PUBMED: 17434869

  • TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population.

    Loos RJ, Franks PW, Francis RW, Barroso I, Gribble FM, Savage DB, Ong KK, O'Rahilly S and Wareham NJ

    Diabetes 2007;56;7;1943-7

    PUBMED: 17416797; PMC: 2668957

  • Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes.

    Tan K, Kimber WA, Luan J, Soos MA, Semple RK, Wareham NJ, O'Rahilly S and Barroso I

    Diabetes 2007;56;3;714-9

    PUBMED: 17327441; PMC: 2672155

  • Lamin A/C polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies.

    Mesa JL, Loos RJ, Franks PW, Ong KK, Luan J, O'Rahilly S, Wareham NJ and Barroso I

    Diabetes 2007;56;3;884-9

    PUBMED: 17327461; PMC: 2668858

  • Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

    Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE and O'Rahilly S

    The New England journal of medicine 2007;356;3;237-47

    PUBMED: 17229951; PMC: 2670197

  • Adiponectin receptor genes: mutation screening in syndromes of insulin resistance and association studies for type 2 diabetes and metabolic traits in UK populations.

    Collins SC, Luan J, Thompson AJ, Daly A, Semple RK, O'Rahilly S, Wareham NJ and Barroso I

    Diabetologia 2007;50;3;555-62

    PUBMED: 17216283; PMC: 1794135

  • Polymorphisms in the gene encoding sterol regulatory element-binding factor-1c are associated with type 2 diabetes.

    Harding AH, Loos RJ, Luan J, O'Rahilly S, Wareham NJ and Barroso I

    Diabetologia 2006;49;11;2642-8

    PUBMED: 17019602; PMC: 2668914

  • PARL Leu262Val is not associated with fasting insulin levels in UK populations.

    Fawcett KA, Wareham NJ, Luan J, Syddall H, Cooper C, O'Rahilly S, Day IN, Sandhu MS and Barroso I

    Diabetologia 2006;49;11;2649-52

    PUBMED: 17019603; PMC: 2672784

  • Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.

    Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, Rajanayagam O, Semple R, Luan J, Bath L, Zalin A, Labib M, Kumar S, Simpson H, Blom D, Marais D, Schwabe J, Barroso I, Trembath R, Wareham N, Nagy L, Gurnell M, O'Rahilly S and Chatterjee K

    Cell metabolism 2006;4;4;303-11

    PUBMED: 17011503; PMC: 1821092

  • Genetic factors in type 2 diabetes: the end of the beginning?

    O'Rahilly S, Barroso I and Wareham NJ

    Science (New York, N.Y.) 2005;307;5708;370-3

    PUBMED: 15662000

  • Genetics of Type 2 diabetes.

    Barroso I

    Diabetic medicine : a journal of the British Diabetic Association 2005;22;5;517-35

    PUBMED: 15842505

  • A family with severe insulin resistance and diabetes due to a mutation in AKT2.

    George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S and Barroso I

    Science (New York, N.Y.) 2004;304;5675;1325-8

    PUBMED: 15166380; PMC: 2258004

  • Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.

    Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O'Rahilly S and Wareham NJ

    PLoS biology 2003;1;1;E20

    PUBMED: 14551916; PMC: 212698

  • Digenic inheritance of severe insulin resistance in a human pedigree.

    Savage DB, Agostini M, Barroso I, Gurnell M, Luan J, Meirhaeghe A, Harding AH, Ihrke G, Rajanayagam O, Soos MA, George S, Berger D, Thomas EL, Bell JD, Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, O'Rahilly S, Chatterjee VK and Schafer AJ

    Nature genetics 2002;31;4;379-84

    PUBMED: 12118251

  • Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension.

    Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK and O'Rahilly S

    Nature ;402;6764;880-3

    PUBMED: 10622252