McCarthy group

Research Overview

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)DIAGRAM

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.

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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.

MAGIC

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.

 

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Selected Recent Publications

Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, Strawbridge RJ, Khan H et al. 2012. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet, 44 (9), pp. 981-990.

Thanabalasingham G, Pal A, Selwood MP, Dudley C, Fisher K, Bingley PJ, Ellard S, Farmer AJ, McCarthy MI, Owen KR. 2012. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care, 35 (6), pp. 1206-1212.

Rob Taal H, Mook-Kanamori DO, Ikram MA, Hofman A, Rivadeneira F, Struchalin M, Vernooij MW, Van Duijn CM et al. 2012. Common variants at 12q15 and 12q24 are associated with infant head circumference Nature Genetics, 44 (5), pp. 532-538.

Scott RA, Luan J, Forouhi NG, Loos RJF, Wareham NJ, Langenberg C, Lagou V, MäGi R et al. 2012. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways Nature Genetics, 44 (9), pp. 991-1005. 

More publications ...

Research Areas

Genetics of type 2 diabetes, obesity and related traits

Keywords

Association analysis, type 2 diabetes, body mass index, obesity, central adiposity, glycaemia, birth weight, fine-mapping, resequencing, translational medicine, CNV