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Insights into the Genetic Susceptibility to Type 2 Diabetes from Genome-Wide Association Studies of Glycaemic Traits

  • Genetics (AP Morris, Section Editor)
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Abstract

Over the past 8 years, the genetics of complex traits have benefited from an unprecedented advancement in the identification of common variant loci for diseases such as type 2 diabetes (T2D). The ability to undertake genome-wide association studies in large population-based samples for quantitative glycaemic traits has permitted us to explore the hypothesis that models arising from studies in non-diabetic individuals may reflect mechanisms involved in the pathogenesis of diabetes. Amongst 88 T2D risk and 72 glycaemic trait loci, only 29 are shared and show disproportionate magnitudes of phenotypic effects. Important mechanistic insights have been gained regarding the physiological role of T2D loci in disease predisposition through the elucidation of their contribution to glycaemic trait variability. Further investigation is warranted to define causal variants within these loci, including functional characterisation of associated variants, to dissect their role in disease mechanisms and to enable clinical translation.

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Acknowledgments

Research of Letizia Marullo was funded by 2010–2011 PRIN funds of the University of Ferrara—Holder: Prof. Guido Barbujani—and in part sponsored by the European Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowships for Young Scientists and by the fund promoting internationalisation efforts of the University of Ferrara—Holder: Prof. Chiara Scapoli.

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Letizia Marullo, Julia S. El-Sayed Moustafa and Inga Prokopenko declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Inga Prokopenko.

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Heatmap of the effects of 88 T2D and 72 glycaemic loci (of which 29 are overlapping, for a total of 131 loci) on T2D and glycaemic traits from published GWA meta-analyses (FG [52•], FI [52•], FIadjBMI [52•], FP [61••], 2hGlu [58••], HOMA-B [52•] and HOMA-IR [52•], HbA1c [60••], CIR [64••], T2D [55•]), secondary signals for six T2D loci are also reported.Legend. We considered established associated variants in a context of genetic loci, where each locus represents a region of less than 300 kb containing one or more SNPs associated with T2D, glycaemic traits or both and with an LD value of r2 > 0.02. A secondary signal in the same locus lies within 300 kb from an originally established signal, but has an LD value of r2 < 0.02 with the primary associated top variant. We have reported the strength and direction of associations from the discovery meta-analyses of GWA studies, therefore, the sample sizes were usually smaller than those reported after the replication or within combined analyses. Hence, for some loci, established associations, reported in the literature, were not genome-wide significant in the discovery GWA meta-analyses used for the heatmap: we thus listed all established associations as exceeding the genome-wide significance threshold (P = 5 × 10−8). Eleven (DUSP9, TCERG1L, MYL2, IGF2, PAM, RBM43/RND3, OAS1, C12orf51, SGCG, HNF1B, SLC16A13/SLC16A11) loci and two (PAM, CCND2) secondary signals are not reported in the figure due to missing data for five or more phenotypes. FG fasting glucose, FI fasting insulin, FP fasting proinsulin, FIadjBMI fasting insulin adjusted for BMI, 2hGlu two-hour post-prandial glucose, 1hGlu one-hour post-prandial glucose, HbA 1c glycated haemoglobin, HOMA-B homeostasis model assessment of β-cell function, HOMA-IR homeostasis model assessment of insulin resistance, CIR corrected insulin response to glucose, adjBMI adjusted for BMI. (GIF 171 kb)

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Marullo, L., El-Sayed Moustafa, J.S. & Prokopenko, I. Insights into the Genetic Susceptibility to Type 2 Diabetes from Genome-Wide Association Studies of Glycaemic Traits. Curr Diab Rep 14, 551 (2014). https://doi.org/10.1007/s11892-014-0551-8

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