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From Genetic Association to Molecular Mechanism

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Abstract

Over the past 3 years, there has been a dramatic increase in the number of confirmed type 2 diabetes (T2D) susceptibility loci, most arising through the implementation of genome-wide association studies (GWAS). However, progress toward the understanding of disease mechanisms has been slowed by modest effect sizes and the fact that most GWAS signals map away from coding sequence: the presumption is that their effects are mediated through regulation of nearby transcripts, but the identities of the genes concerned are often far from clear. In this review we describe the progress that has been made to date in translating association signals into molecular mechanisms with a focus on the most tractable signals (eg, KCNJ11/ABCC8, SLC30A8, GCKR) and those in which human, animal, and cellular models (FTO, TCF7L2, G6PC2) have provided insights into the role in T2D pathogenesis. Finally, the challenges for the field with the advent of genome-scale next-generation resequencing efforts are discussed.

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Acknowledgments

We apologize to the colleagues whose work we could not cite here because of space limitations. Dr. Anna L. Gloyn is a Medical Research Council (MRC) New investigator (Grant Code 81696). Dr. Martijn van de Bunt is a Nuffield Department of Medicine Prize Student. Projects in the Gloyn laboratory are funded by the MRC and Diabetes UK.

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  1. Diabetes Research Laboratories, Oxford Centre for Diabetes Endocrinology & Metabolism, Churchill Hospital, University of Oxford, Headington, Oxford, OX3 7LJ, UK

    Martijn van de Bunt & Anna L. Gloyn

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  1. Martijn van de Bunt
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Correspondence to Anna L. Gloyn.

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van de Bunt, M., Gloyn, A.L. From Genetic Association to Molecular Mechanism. Curr Diab Rep 10, 452–466 (2010). https://doi.org/10.1007/s11892-010-0150-2

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