Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Gaulton, K. J. et al. (2015) Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nature Genetics, 47(12), pp. 1415-1425. (doi:10.1038/ng.3437) (PMID:26551672) (PMCID:MC4666734)

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Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strawbridge, Dr Rona
Authors: Gaulton, K. J., Ferreira, T., Lee, Y., Raimondo, A., Mägi, R., Reschen, M. E., Mahajan, A., Locke, A., William Rayner, N., Robertson, N., Scott, R. A., Prokopenko, I., Scott, L. J., Green, T., Sparso, T., Thuillier, D., Yengo, L., Grallert, H., Wahl, S., Frånberg, M., Strawbridge, R. J., Kestler, H., Chheda, H., Eisele, L., Gustafsson, S., Steinthorsdottir, V., Thorleifsson, G., Qi, L., Karssen, L. C., van Leeuwen, E. M., Willems, S. M., Li, M., Chen, H., Fuchsberger, C., Kwan, P., Ma, C., Linderman, M., Lu, Y., Thomsen, S. K., Rundle, J. K., Beer, N. L., van de Bunt, M., Chalisey, A., Kang, H. M., Voight, B. F., Abecasis, G. R., Almgren, P., Baldassarre, D., Balkau, B., Benediktsson, R., Blüher, M., Boeing, H., Bonnycastle, L. L., Bottinger, E. P., Burtt, N. P., Carey, J., Charpentier, G., Chines, P. S., Cornelis, M. C., Couper, D. J., Crenshaw, A. T., van Dam, R. M., Doney, A. S. F., Dorkhan, M., Edkins, S., Eriksson, J. G., Esko, T., Eury, E., Fadista, J., Flannick, J., Fontanillas, P., Fox, C., Franks, P. W., Gertow, K., Gieger, C., Gigante, B., Gottesman, O., Grant, G. B., Grarup, N., Groves, C. J., Hassinen, M., Have, C. T., Herder, C., Holmen, O. L., Hreidarsson, A. B., Humphries, S. E., Hunter, D. J., Jackson, A. U., Jonsson, A., Jørgensen, M. E., Jørgensen, T., Kao, W.-H. L., Kerrison, N. D., Kinnunen, L., Klopp, N., Kong, A., Kovacs, P., Kraft, P., Kravic, J., Langford, C., Leander, K., Liang, L., Lichtner, P., Lindgren, C. M., Lindholm, E., Linneberg, A., Liu, C.-T., Lobbens, S., Luan, J.'a., Lyssenko, V., Männistö, S., McLeod, O., Meyer, J., Mihailov, E., Mirza, G., Mühleisen, T. W., Müller-Nurasyid, M., Navarro, C., Nöthen, M. M., Oskolkov, N. N., Owen, K. R., Palli, D., Pechlivanis, S., Peltonen, L., Perry, J. R. B., Platou, C. G. P., Roden, M., Ruderfer, D., Rybin, D., van der Schouw, Y. T., Sennblad, B., Sigurðsson, G., Stančáková, A., Steinbach, G., Storm, P., Strauch, K., Stringham, H. M., Sun, Q., Thorand, B., Tikkanen, E., Tonjes, A., Trakalo, J., Tremoli, E., Tuomi, T., Wennauer, R., Wiltshire, S., Wood, A. R., Zeggini, E., Dunham, I., Birney, E., Pasquali, L., Ferrer, J., Loos, R. J. F., Dupuis, J., Florez, J. C., Boerwinkle, E., Pankow, J. S., van Duijn, C., Sijbrands, E., Meigs, J. B., Hu, F. B., Thorsteinsdottir, U., Stefansson, K., Lakka, T. A., Rauramaa, R., Stumvoll, M., Pedersen, N. L., Lind, L., Keinanen-Kiukaanniemi, S. M., Korpi-Hyövälti, E., Saaristo, T. E., Saltevo, J., Kuusisto, J., Laakso, M., Metspalu, A., Erbel, R., Jöcke, K.-H., Moebus, S., Ripatti, S., Salomaa, V., Ingelsson, E., Boehm, B. O., Bergman, R. N., Collins, F. S., Mohlke, K. L., Koistinen, H., Tuomilehto, J., Hveem, K., Njølstad, I., Deloukas, P., Donnelly, P. J., Frayling, T. M., Hattersley, A. T., de Faire, U., Hamsten, A., Illig, T., Peters, A., Cauchi, S., Sladek, R., Froguel, P., Hansen, T., Pedersen, O., Morris, A. D., Palmer, C. N. A., Kathiresan, S., Melander, O., Nilsson, P. M., Groop, L. C., Barroso, I., Langenberg, C., Wareham, N. J., O'Callaghan, C. A., Gloyn, A. L., Altshuler, D., Boehnke, M., Teslovich, T. M., McCarthy, M. I., and Morris, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:09 November 2015

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