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Diabetes DOI:10.2337/db16-1253

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

Publication TypeJournal Article
Year of Publication2017
AuthorsScott, RA, Scott, LJ, Mägi, R, Marullo, L, Gaulton, KJ, Kaakinen, M, Pervjakova, N, Pers, TH, Johnson, AD, Eicher, JD, Jackson, AU, Ferreira, T, Lee, Y, Ma, C, Steinthorsdottir, V, Thorleifsson, G, Qi, L, van Zuydam, NR, Mahajan, A, Chen, H, Almgren, P, Voight, BF, Grallert, H, Müller-Nurasyid, M, Ried, JS, Rayner, NW, Robertson, N, Karssen, LC, van Leeuwen, EM, Willems, SM, Fuchsberger, C, Kwan, P, Teslovich, TM, Chanda, P, Li, M, Lu, Y, Dina, C, Thuillier, D, Yengo, L, Jiang, L, Sparso, T, Kestler, HA, Chheda, H, Eisele, L, Gustafsson, S, Frånberg, M, Strawbridge, RJ, Benediktsson, R, Hreidarsson, AB, Kong, A, Sigurðsson, G, Kerrison, ND, Luan, J'an, Liang, L, Meitinger, T, Roden, M, Thorand, B, Esko, T, Mihailov, E, Fox, C, Liu, C-T, Rybin, D, Isomaa, B, Lyssenko, V, Tuomi, T, Couper, DJ, Pankow, JS, Grarup, N, Have, CT, Jørgensen, ME, Jørgensen, T, Linneberg, A, Cornelis, MC, van Dam, RM, Hunter, DJ, Kraft, P, Sun, Q, Edkins, S, Owen, KR, Perry, JRB, Wood, AR, Zeggini, E, Tajes-Fernandes, J, Abecasis, GR, Bonnycastle, LL, Chines, PS, Stringham, HM, Koistinen, HA, Kinnunen, L, Sennblad, B, Mühleisen, TW, Nöthen, MM, Pechlivanis, S, Baldassarre, D, Gertow, K, Humphries, SE, Tremoli, E, Klopp, N, Meyer, J, Steinbach, G, Wennauer, R, Eriksson, JG, Mӓnnistö, S, Peltonen, L, Tikkanen, E, Charpentier, G, Eury, E, Lobbens, S, Gigante, B, Leander, K, McLeod, O, Bottinger, EP, Gottesman, O, Ruderfer, D, Blüher, M, Kovacs, P, Tönjes, A, Maruthur, NM, Scapoli, C, Erbel, R, Jöckel, K-H, Moebus, S, de Faire, U, Hamsten, A, Stumvoll, M, Deloukas, P, Donnelly, PJ, Frayling, TM, Hattersley, AT, Ripatti, S, Salomaa, V, Pedersen, NL, Boehm, BO, Bergman, RN, Collins, FS, Mohlke, KL, Tuomilehto, J, Hansen, T, Pedersen, O, Barroso, I, Lannfelt, L, Ingelsson, E, Lind, L, Lindgren, CM, Cauchi, S, Froguel, P, Loos, RJF, Balkau, B, Boeing, H, Franks, PW, Gurrea, ABarricarte, Palli, D, van der Schouw, YT, Altshuler, D, Groop, LC, Langenberg, C, Wareham, NJ, Sijbrands, E, van Duijn, CM, Florez, JC, Meigs, JB, Boerwinkle, E, Gieger, C, Strauch, K, Metspalu, A, Morris, AD, Palmer, CNA, Hu, FB, Thorsteinsdottir, U, Stefansson, K, Dupuis, J, Morris, AP, Boehnke, M, McCarthy, MI, Prokopenko, I
Corporate AuthorsDIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
JournalDiabetes
Volume66
Issue11
Pages2888-2902
Date Published2017 11
ISSN1939-327X
KeywordsDiabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans
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 ( < 5 × 10), including variants near the , , and 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.

DOI10.2337/db16-1253
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28566273?dopt=Abstract

Alternate JournalDiabetes
PubMed ID28566273
PubMed Central IDPMC5652602
Grant ListR01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
R01 DK073490 / DK / NIDDK NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
098017 / / Wellcome Trust / United Kingdom
R01 DK058845 / DK / NIDDK NIH HHS / United States
RG/08/008/25291 / / British Heart Foundation / United Kingdom
N01HG65403 / HG / NHGRI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 DK085545 / DK / NIDDK NIH HHS / United States
R01 DK106236 / DK / NIDDK NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 DK098032 / DK / NIDDK NIH HHS / United States
ZIA HG000024 / HG / NHGRI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HG000376 / HG / NHGRI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
MC_UU_12015/1 / / Medical Research Council / United Kingdom
U01 DK105535 / DK / NIDDK NIH HHS / United States
R01 DK101478 / DK / NIDDK NIH HHS / United States
P30 DK046200 / DK / NIDDK NIH HHS / United States
R01 AG028555 / AG / NIA NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
MC_UU_12015/2 / / Medical Research Council / United Kingdom
HHSN268201100005I / HL / NHLBI NIH HHS / United States
RC2 DK088389 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
MR/M501633/2 / / Medical Research Council / United Kingdom
U01 DK078616 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
RG/14/5/30893 / / British Heart Foundation / United Kingdom
MR/K007017/1 / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
R01 AG033067 / AG / NIA NIH HHS / United States
MC_PC_13040 / / Medical Research Council / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States
G0601261 / / Medical Research Council / United Kingdom
R01 AG010175 / AG / NIA NIH HHS / United States
U01 HG004399 / HG / NHGRI NIH HHS / United States
MR/M501633/1 / / Medical Research Council / United Kingdom