Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Mahajan, A. et al. (2018) Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nature Genetics, 50(4), pp. 559-571. (doi:10.1038/s41588-018-0084-1) (PMID:29632382)

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Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10 ); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Young, Dr Robin and Sattar, Professor Naveed
Authors: Mahajan, A., Wessel, J., Willems, S. M., Zhao, W., Robertson, N. R., Chu, A. Y., Gan, W., Kitajima, H., Taliun, D., Rayner, N. W., Guo, X., Lu, Y., Li, M., Jensen, R. A., Hu, Y., Huo, S., Lohman, K. K., Zhang, W., Cook, J. P., Prins, B. P., Flannick, J., Grarup, N., Trubetskoy, V. V., Kravic, J., Kim, Y. J., Rybin, D. V., Yaghootkar, H., Müller-Nurasyid, M., Meidtner, K., Li-Gao, R., Varga, T. V., Marten, J., Li, J., Smith, A. V., An, P., Ligthart, S., Gustafsson, S., Malerba, G., Demirkan, A., Tajes, J. F., Steinthorsdottir, V., Wuttke, M., Lecoeur, C., Preuss, M., Bielak, L. F., Graff, M., Highland, H. M., Justice, A. E., Liu, D. J., Marouli, E., Peloso, G. M., Warren, H. R., Afaq, S., Afzal, S., Ahlqvist, E., Almgren, P., Amin, N., Bang, L. B., Bertoni, A. G., Bombieri, C., Bork-Jensen, J., Brandslund, I., Brody, J. A., Burtt, N. P., Canouil, M., Chen, Y.-D. I., Cho, Y. S., Christensen, C., Eastwood, S. V., Eckardt, K.-U., Fischer, K., Gambaro, G., Giedraitis, V., Grove, M. L., de Haan, H. G., Hackinger, S., Hai, Y., Han, S., Tybjærg-Hansen, A., Hivert, M.-F., Isomaa, B., Jäger, S., Jørgensen, M. E., Jørgensen, T., Käräjämäki, A., Kim, B.-J., Kim, S. S., Koistinen, H. A., Kovacs, P., Kriebel, J., Kronenberg, F., Läll, K., Lange, L. A., Lee, J.-J., Lehne, B., Li, H., Lin, K.-H., Linneberg, A., Liu, C.-T., Liu, J., Loh, M., Mägi, R., Mamakou, V., McKean-Cowdin, R., Nadkarni, G., Neville, M., Nielsen, S. F., Ntalla, I., Peyser, P. A., Rathmann, W., Rice, K., Rich, S. S., Rode, L., Rolandsson, O., Schönherr, S., Selvin, E., Small, K. S., Stančáková, A., Surendran, P., Taylor, K. D., Teslovich, T. M., Thorand, B., Thorleifsson, G., Tin, A., Tönjes, A., Varbo, A., Witte, D. R., Wood, A. R., Yajnik, P., Yao, J., Yengo, L., Young, R., Amouyel, P., Boeing, H., Boerwinkle, E., Bottinger, E. P., Chowdhury, R., Collins, F. S., Dedoussis, G., Dehghan, A., Deloukas, P., Ferrario, M. M., Ferrières, J., Florez, J. C., Frossard, P., Gudnason, V., Harris, T. B., Heckbert, S. R., Howson, J. M. M., Ingelsson, M., Kathiresan, S., Kee, F., Kuusisto, J., Langenberg, C., Launer, L. J., Lindgren, C. M., Männistö, S., Meitinger, T., Melander, O., Mohlke, K. L., Moitry, M., Morris, A. D., Murray, A. D., de Mutsert, R., Orho-Melander, M., Owen, K. R., Perola, M., Peters, A., Province, M. A., Rasheed, A., Ridker, P. M., Rivadineira, F., Rosendaal, F. R., Rosengren, A. H., Salomaa, V., Sheu, W. H.-H., Sladek, R., Smith, B. H., Strauch, K., Uitterlinden, A. G., Varma, R., Willer, C. J., Blüher, M., Butterworth, A. S., Chambers, J. C., Chasman, D. I., Danesh, J., van Duijn, C., Dupuis, J., Franco, O. H., Franks, P. W., Froguel, P., Grallert, H., Groop, L., Han, B.-G., Hansen, T., Hattersley, A. T., Hayward, C., Ingelsson, E., Kardia, S. L. R., Karpe, F., Kooner, J. S., Köttgen, A., Kuulasmaa, K., Laakso, M., Lin, X., Lind, L., Liu, Y., Loos, R. J. F., Marchini, J., Metspalu, A., Mook-Kanamori, D., Nordestgaard, B. G., Palmer, C. N. A., Pankow, J. S., Pedersen, O., Psaty, B. M., Rauramaa, R., Sattar, N., Schulze, M. B., Soranzo, N., Spector, T. D., Stefansson, K., Stumvoll, M., Thorsteinsdottir, U., Tuomi, T., Tuomilehto, J., Wareham, N. J., Wilson, J. G., Zeggini, E., Scott, R. A., Barroso, I., Frayling, T. M., Goodarzi, M. O., Meigs, J. B., Boehnke, M., Saleheen, D., Morris, A. P., Rotter, J. I., and McCarthy, M. I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:09 April 2018
Copyright Holders:Copyright © 2018 Nature America Inc., part of Springer Nature
First Published:First published in Nature Genetics 50(4): 559-571
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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