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An expanded genome-wide association study of Type 2 diabetes in Europeans

Title: An expanded genome-wide association study of Type 2 diabetes in Europeans
Authors: Scott, RA
Scott, LJ
Mägi, R
Marullo, L
Gaulton, KJ
Kaakinen, M
Pervjakova, N
Pers, TH
Johnson, AD
Eicher, JD
Jackson, AU
Ried, JS
Rayner, WN
Robertson, N
Karssen, LC
Van Leeuwen, EM
Willems, SM
Fuchsberger, C
Kwan, P
Teslovich, TM
Chanda, P
Wennauer, R
Li, M
Lu, Y
Dina, C
Thuillier, D
Yengo, L
Jiang, L
Sparso, T
Kestler, HA
Chheda, H
Eisele, L
Eriksson, JG
Gustafsson, S
Frånberg, M
Strawbridge, RJ
Benediktsson, R
Hreidarsson, AB
Kong, A
Sigurðsson, G
Kerrison, ND
Luan, J
Liang, L
Mӓnnistö, S
Meitinger, T
Roden, M
Thorand, B
Esko, T
Mihailov, E
Fox, C
Liu, CT
Rybin, D
Isomaa, B
Lyssenko, V
Peltonen, L
Tuomi, T
Couper, DJ
Pankow, JS
Grarup, N
Have, CT
Jørgensen, ME
Jørgensen, T
Linneberg, A
Cornelis, MC
Van Dam, RM
Tikkanen, E
Hunter, DJ
Kraft, P
Sun, Q
Edkins, S
Owen, KR
Perry, JR
Wood, AR
Zeggini, E
Tajes-Fernandes, J
Abecasis, GR
Charpentier, G
Bonnycastle, LL
Chines, PS
Stringham, HM
Koistinen, HA
Kinnunen, L
Sennblad, B
Mühleisen, TW
Nöthen, MM
Pechlivanis, S
Baldassarre, D
Eury, E
Gertow, K
Humphries, SE
Tremoli, E
Klopp, N
Meyer, J
Steinbach, G
Lobbens, S
Gigante, B
Leander, K
Ferreira, T
McLeod, O
Bottinger, EP
Gottesman, O
Ruderfer, D
Blüher, M
Kovacs, P
Tonjes, A
Maruthur, NM
Scapoli, C
Erbel, R
Lee, Y
Jöckel, KH
Moebus, S
De Faire, U
Hamsten, A
Stumvoll, M
Deloukas, P
Donnelly, PJ
Frayling, TM
Hattersley, AT
Ripatti, S
Ma, C
Salomaa, V
Pedersen, NL
Boehm, BO
Bergman, RN
Collins, FS
Mohlke, KL
Tuomilehto, J
Hansen, T
Pedersen, O
Barroso, I
Steinthorsdottir, V
Lannfelt, L
Ingelsson, E
Lind, L
Lindgren, CM
Cauchi, S
Froguel, P
Loos, RJ
Balkau, B
Boeing, H
Franks, PW
Thorleifsson, G
Gurrea, AB
Palli, D
Van der Schouw, YT
Altshuler, D
Groop, LC
Langenberg, C
Wareham, NJ
Sijbrands, E
Van Duijn, CM
Florez, JC
Qi, L
Meigs, JB
Boerwinkle, E
Gieger, C
Strauch, K
Metspalu, A
Morris, AD
Palmer, CN
Hu, FB
Thorsteinsdottir, U
Stefansson, K
Van Zuydam, NR
Dupuis, J
Morris, AP
Boehnke, M
McCarthy, MI
Prokopenko, I
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Mahajan, A
Chen, H
Almgren, P
Voight, BF
Grallert, H
Müller-Nurasyid, M
Item Type: Journal Article
Abstract: To characterise 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 cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). 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 SNVs. 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.
Issue Date: 31-May-2017
Date of Acceptance: 20-May-2017
URI: http://hdl.handle.net/10044/1/49274
DOI: https://dx.doi.org/10.2337/db16-1253
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 2888
End Page: 2902
Journal / Book Title: Diabetes
Volume: 66
Issue: 11
Copyright Statement: © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Sponsor/Funder: Commission of the European Communities
Commission of the European Communities
Wellcome Trust
Funder's Grant Number: 626461
633595
205915/Z/17/Z
Keywords: DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
11 Medical And Health Sciences
Endocrinology & Metabolism
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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