An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Robert A. Scott, Laura J. Scott, Reedik Maegi, Letizia Marullo, Kyle J. Gaulton, Marika Kaakinen, Natalia Pervjakova, Tune H. Pers, Andrew D. Johnson, John D. Eicher, Anne U. Jackson, Teresa Ferreira, Yeji Lee, Clement Ma, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Lu Qi, Natalie R. Van Zuydam, Anubha Mahajan, Han ChenPeter Almgren, Ben F. Voight, Harald Grallert, Martina Mueller-Nurasyid, Janina S. Ried, Nigel W. Rayner, Neil Robertson, Lennart C. Karssen, Elisabeth M. Van Leeuwen, Sara M. Willems, Christian Fuchsberger, Phoenix Kwan, Tanya M. Teslovich, Pritam Chanda, Man Li, Yingchang Lu, Christian Dina, Dorothee Thuillier, Loic Yengo, Longda Jiang, Thomas Sparso, Hans A. Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Mattias Franberg, Rona J. Strawbridge, Rafn Benediktsson, Andrew D. Morris, Colin N. A. Palmer, for the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

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Abstract

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Original languageEnglish
Pages (from-to)2888-2902
Number of pages15
JournalDiabetes
Volume66
Issue number11
Early online date31 May 2017
DOIs
Publication statusPublished - Nov 2017

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Scott, R. A., Scott, L. J., Maegi, R., Marullo, L., Gaulton, K. J., Kaakinen, M., Pervjakova, N., Pers, T. H., Johnson, A. D., Eicher, J. D., Jackson, A. U., Ferreira, T., Lee, Y., Ma, C., Steinthorsdottir, V., Thorleifsson, G., Qi, L., Van Zuydam, N. R., Mahajan, A., ... for the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium (2017). An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes, 66(11), 2888-2902. https://doi.org/10.2337/db16-1253