Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Mahajan, A. et al. (2018) Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nature Genetics, 50, pp. 1505-1513. (doi:10.1038/s41588-018-0241-6) (PMID:30297969)

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Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sattar, Professor Naveed and Ford, Professor Ian
Authors: Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., Payne, A. J., Steinthorsdottir, V., Scott, R. A., Grarup, N., Cook, J. P., Schmidt, E. M., Wuttke, M., Sarnowski, C., Mägi, R., Nano, J., Gieger, C., Trompet, S., Lecoeur, C., Preuss, M. H., Prins, B. P., Guo, X., Bielak, L. F., Below, J. E., Bowden, D. W., Chambers, J. C., Kim, Y. J., Ng, M. C. Y., Petty, L. E., Sim, X., Zhang, W., Bennett, A. J., Bork-Jensen, J., Brummett, C. M., Canouil, M., Ec kardt, K.-U., Fischer, K., Kardia, S. L. R., Kronenberg, F., Läll, K., Liu, C.-T., Locke, A. E., Luan, J.’a., Ntalla, I., Nylander, V., Schönherr, S., Schurmann, C., Yengo, L., Bottinger, E. P., Brandslund, I., Christensen, C., Dedoussis, G., Florez, J. C., Ford, I., Franco, O. H., Frayling, T. M., Giedraitis, V., Hackinger, S., Hattersley, A. T., Herder, C., Ikram, M. A., Ingelsson, M., Jørgensen, M. E., Jørgensen, T., Kriebel, J., Kuusisto, J., Ligthart, S., Lindgren, C. M., Linneberg, A., Lyssenko, V., Mamakou, V., Meitinger, T., Mohlke, K. L., Morris, A. D., Nadkarni, G., Pankow, J. S., Peters, A., Sattar, N., Stančáková, A., Strauch, K., Taylor, K. D., Thorand, B., Thorleifsson, G., Thorsteinsdottir, U., Tuomilehto, J., Witte, D. R., Dupuis, J., Peyser, P. A., Zeggini, E., Loos, R. J. F., Froguel, P., Ingelsson, E., Lind, L., Groop, L., Laakso, M., Collins, F. S., Jukema, J. W., Palmer, C. N. A., Grallert, H., Metspalu, A., Dehghan, A., Köttgen, A., Abecasis, G. R., Meigs, J. B., Rotter, J. I., Marchini, J., Pedersen, O., Hansen, T., Langenberg, C., Wareham, N. J., Stefansson, K., Gloyn, A. L., Morris, A. P., Boehnke, M., and McCarthy, M. I.
College/School:College of Science and Engineering > School of Engineering > Electronics and Nanoscale Engineering
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:08 October 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Nature Genetics 50:1505-1513
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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