The McCarthy group has a primary interest in using genetic approaches to understand a genetic background underlying susceptibility and pathogenesis of type 2 diabetes and related phenotypes including obesity and glycaemia.
The group is based at Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), a pioneering centre combining clinical care, research and education in diabetes, endocrine and metabolic diseases, and Wellcome Trust Centre for Human Genetics in Oxford, a world known centre of scientific excellence for studies in the field of human genetics.
The group has strong background in large-scale genetic analysis and is involved in several major international consortia including the Wellcome Trust Case Control Consortium (WTCCC, genome-wide association studies), DIAGRAM (T2D genetics), EU-funded ENGAGE consortium (www.euengage.org), GIANT (anthropometric traits), MAGIC (continuous glycaemic traits), EGG (early growth genetics), International 1q Consortium (a coordinated effort by the groups with the strongest evidence for 1q linkage in T2D).
With the appearance and diffusion of the whole genome genotyping platforms, the large scale genetic association studies have become one of the main approaches for gene identification in complex human disorders. This technological and analytical advancement has enabled scientists from our and other groups within WTCCC to perform one of the first successful Genome Wide Association studies on 7 human complex multifactorial phenotypes, where 6 variants were identified and confirmed as predisposing to type 2 diabetes (T2D) based on the ~500,000 SNPs and a sample of 2,000 cases and 3,000 controls of Northern European origin(UK).
Subsequent collaboration with two other research groups within DIAGRAM consortium has allowed us to improve power of the study by combining three T2D GWA scans (WTCCC T2D, DGI and FUSION) for a total of 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed) and to identify 6 novel T2D susceptibility genes (PMID: 18372903).
Current collaboration within DIAGRAM+ consortium involves 8 groups with T2D GWA scans (recently joined deCODE, KORA, Rotterdam, EUROSPAN, French) for a total of ~19,000 individuals included for meta-analysis of GW imputed data.
Ongoing efforts performed by our group to unravel the causal variants in the new confirmed T2D susceptibility loci include fine-mapping, large-scale resequencing, methylation, and metabonomics studies.
Availability of GW data for large population-based cohorts of healthy individuals with large quantity of phenotypic data (i.e. anthropometric, blood examination, biofluids, DXA scans etc. taken at one time-point or in longitudinal fashion) has allowed us to investigate the impact of various quantitative traits related to T2D, among them measures of obesity and glycaemia.
Collaboration within GIANT consortium has contributed to the identification of 6 obesity loci (TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, and NEGR1) in addition to FTO and MC4R identified by our group within various collaborations. Genome wide meta-analyses of other obesity and anthropometric traits yielded identification of many new loci contributing to the variability of these quantitative traits.
Integration of GWA data for fasting glycaemic traits in normoglycaemic subjects in 36,610 individuals of European descent from population-based samples within MAGIC consortium allowed us to identify novel locus associated with increased levels of Fasting Glucose at MTNR1B, know to be involved in the circadian regulation. This locus has also been shown to contribute to the T2D susceptibility (PMID: 19060907). At present MAGIC consortium endeavored investigation of Fasting Glucose and Fasting Insulin, HbA1c, 2h OGTT in large meta-analyses of healthy subjects aiming to dissect genetic variability between loci predisposing to physiological or to pathological changes in glycaemic traits levels.
Integration and meta-analysis of existing and future large-scale genetic data and integration of other data types (CNV data, resequencing, expression, metabonomics etc) are the approaches currently applied and used by our group to deepen the knowledge about genetics of T2D diabetes and related traits.
Selected Recent Publications
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JRB, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch A-M, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin M-R, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJF, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CNA, Doney ASF, Morris AD, Davey-Smith G, The Wellcome Trust Case Control Consortium, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007;316:889-894 PMID: 17434869
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, De Bakker PW, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding C, Doney ASF, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup, Groves CJ, Giuducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jorgensen 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 CNA, Payne F, Perry JRB, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjogren 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 FN, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI*, Boehnke M*, Altshuler D*. Meta-analysis of genome-wide association data and large-scale replication identifies several additional susceptibility loci for type 2 diabetes Nature Genetics 2008; 40:638-645 PMID: 18372903
Loos RJF, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Davey Smith G, Day I, Dina C, De S, Dermitzakis ET, Doney ASD, Elliott KS, Elliott P, Evans DM, Farooqi IS, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid RM, KORA, Herrera B, Hinney A, Hunt SE, Jarvelin M-R, Johnson T, Jolley JDM, Karpe F, Keniry A, Khaw K-T, Luben RN, Mangino MN, 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 CNA, 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 CIG, Wallace C, Waterworth DM, Weedon MN, The Wellcome Trust Case Control Consortium, Willer CJ, FUSION, Wraight VL, 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*. Association studies involving over 90,000 people demonstrate that common variants near to MC4R influence fat mass, weight and risk of obesity. Nature Genetics 2008;40:768-775 PMID: 18454148
McCarthy MI, Abecasis G, Cardon LR, Little J, Ioannidis JPA, Goldstein DB, Hirschhorn JN. Genome wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics 2008;9:356-369 PMID: 18398418
Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJF, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga J-J, Wheeler E, Kaakinen M, Lyssenko V, Chen W-M, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, De Geus EJC, Dehghan A, Deloukas P, Doney ASF, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT, Mohlke KL, Morris AD, Naitza S, Orru M, Palmer CNA, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann H-E, Willemsen G, Witteman JCM, Yuan X, Zao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma D, Uda M, Spector TD, Penninx BWJH, Altshuler D, Vollenweider P, Jarvelin M-R, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR. Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels. Nature Genetics 2009;41:77-81 PMID: 19060907
Genetics of type 2 diabetes, obesity and related traits
Association analysis, type 2 diabetes, body mass index, obesity, central adiposity, glycaemia, birth weight, fine-mapping, resequencing, translational medicine, CNV