An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.
An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.
复制标题
DOI：
10.2337/db16-1253
复制
发表时间：
2017-11
期刊：
影响因子：
7.7
通讯作者：
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
中科院分区：
文献类型：
--
作者：
Scott 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;Liang L;Meitinger T;Roden M;Thorand B;Esko T;Mihailov E;Fox C;Liu CT;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;Tonjes A;Maruthur NM;Scapoli C;Erbel R;Jöckel KH;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;Barricarte Gurrea A;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;DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
为了表征2型糖尿病（T2 D）相关的等位基因频率谱变异，我们使用1000个基因组多种族参考面板对来自欧洲血统的26，676例T2 D病例和132，532例对照受试者的全基因组关联数据进行了荟萃分析。在其他数据集中（14，545或7，397例T2 D病例和38，994或71，604例对照受试者）随访了有希望的相关信号。我们发现了13个新的T2 D相关基因座（P < 5 × 10−8），包括GLP 2 R、GIP和HLA-DQA 1基因附近的变异。我们的分析使独立的T2 D关联总数达到113个位点的128个不同信号。尽管样本量大幅增加，低频变异的覆盖率更高，但所有新的关联都是由常见的单核苷酸变异驱动的。可信的潜在因果变异的集合通常大于基于早期参考组插补的集合，这与因果信号对常见风险单倍型的分辨率一致。基于T2 D相关数量性状关联的T2 D相关位点的分层揭示了胰岛增强子中影响胰岛素分泌的位点和脂肪细胞、单核细胞和肝细胞中胰岛素作用相关位点的调节注释的组织特异性富集。这些发现强调了影响T2 D病理生理学的常见变异体和生物学机制的多样性所发挥的主导作用。
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.
登录
查看更多内容
影响因子：
30.8
作者：
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium;Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium;South Asian Type 2 Diabetes (SAT2D) Consortium;Mexican American Type 2 Diabetes (MAT2D) Consortium;Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium;Mahajan A;Go MJ;Zhang W;Below JE;Gaulton KJ;Ferreira T;Horikoshi M;Johnson AD;Ng MC;Prokopenko I;Saleheen D;Wang X;Zeggini E;Abecasis GR;Adair LS;Almgren P;Atalay M;Aung T;Baldassarre D;Balkau B;Bao Y;Barnett AH;Barroso I;Basit A;Been LF;Beilby J;Bell GI;Benediktsson R;Bergman RN;Boehm BO;Boerwinkle E;Bonnycastle LL;Burtt N;Cai Q;Campbell H;Carey J;Cauchi S;Caulfield M;Chan JC;Chang LC;Chang TJ;Chang YC;Charpentier G;Chen CH;Chen H;Chen YT;Chia KS;Chidambaram M;Chines PS;Cho NH;Cho YM;Chuang LM;Collins FS;Cornelis MC;Couper DJ;Crenshaw AT;van Dam RM;Danesh J;Das D;de Faire U;Dedoussis G;Deloukas P;Dimas AS;Dina C;Doney AS;Donnelly PJ;Dorkhan M;van Duijn C;Dupuis J;Edkins S;Elliott P;Emilsson V;Erbel R;Eriksson JG;Escobedo J;Esko T;Eury E;Florez JC;Fontanillas P;Forouhi NG;Forsen T;Fox C;Fraser RM;Frayling TM;Froguel P;Frossard P;Gao Y;Gertow K;Gieger C;Gigante B;Grallert H;Grant GB;Grrop LC;Groves CJ;Grundberg E;Guiducci C;Hamsten A;Han BG;Hara K;Hassanali N;Hattersley AT;Hayward C;Hedman AK;Herder C;Hofman A;Holmen OL;Hovingh K;Hreidarsson AB;Hu C;Hu FB;Hui J;Humphries SE;Hunt SE;Hunter DJ;Hveem K;Hydrie ZI;Ikegami H;Illig T;Ingelsson E;Islam M;Isomaa B;Jackson AU;Jafar T;James A;Jia W;Jöckel KH;Jonsson A;Jowett JB;Kadowaki T;Kang HM;Kanoni S;Kao WH;Kathiresan S;Kato N;Katulanda P;Keinanen-Kiukaanniemi KM;Kelly AM;Khan H;Khaw KT;Khor CC;Kim HL;Kim S;Kim YJ;Kinnunen L;Klopp N;Kong A;Korpi-Hyövälti E;Kowlessur S;Kraft P;Kravic J;Kristensen MM;Krithika S;Kumar A;Kumate J;Kuusisto J;Kwak SH;Laakso M;Lagou V;Lakka TA;Langenberg C;Langford C;Lawrence R;Leander K;Lee JM;Lee NR;Li M;Li X;Li Y;Liang J;Liju S;Lim WY;Lind L;Lindgren CM;Lindholm E;Liu CT;Liu JJ;Lobbens S;Long J;Loos RJ;Lu W;Luan J;Lyssenko V;Ma RC;Maeda S;Mägi R;Männisto S;Matthews DR;Meigs JB;Melander O;Metspalu A;Meyer J;Mirza G;Mihailov E;Moebus S;Mohan V;Mohlke KL;Morris AD;Mühleisen TW;Müller-Nurasyid M;Musk B;Nakamura J;Nakashima E;Navarro P;Ng PK;Nica AC;Nilsson PM;Njølstad I;Nöthen MM;Ohnaka K;Ong TH;Owen KR;Palmer CN;Pankow JS;Park KS;Parkin M;Pechlivanis S;Pedersen NL;Peltonen L;Perry JR;Peters A;Pinidiyapathirage JM;Platou CG;Potter S;Price JF;Qi L;Radha V;Rallidis L;Rasheed A;Rathman W;Rauramaa R;Raychaudhuri S;Rayner NW;Rees SD;Rehnberg E;Ripatti S;Robertson N;Roden M;Rossin EJ;Rudan I;Rybin D;Saaristo TE;Salomaa V;Saltevo J;Samuel M;Sanghera DK;Saramies J;Scott J;Scott LJ;Scott RA;Segrè AV;Sehmi J;Sennblad B;Shah N;Shah S;Shera AS;Shu XO;Shuldiner AR;Sigurđsson G;Sijbrands E;Silveira A;Sim X;Sivapalaratnam S;Small KS;So WY;Stančáková A;Stefansson K;Steinbach G;Steinthorsdottir V;Stirrups K;Strawbridge RJ;Stringham HM;Sun Q;Suo C;Syvänen AC;Takayanagi R;Takeuchi F;Tay WT;Teslovich TM;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tikkanen E;Trakalo J;Tremoli E;Trip MD;Tsai FJ;Tuomi T;Tuomilehto J;Uitterlinden AG;Valladares-Salgado A;Vedantam S;Veglia F;Voight BF;Wang C;Wareham NJ;Wennauer R;Wickremasinghe AR;Wilsgaard T;Wilson JF;Wiltshire S;Winckler W;Wong TY;Wood AR;Wu JY;Wu Y;Yamamoto K;Yamauchi T;Yang M;Yengo L;Yokota M;Young R;Zabaneh D;Zhang F;Zhang R;Zheng W;Zimmet PZ;Altshuler D;Bowden DW;Cho YS;Cox NJ;Cruz M;Hanis CL;Kooner J;Lee JY;Seielstad M;Teo YY;Boehnke M;Parra EJ;Chambers JC;Tai ES;McCarthy MI;Morris AP
通讯作者：
Morris AP
影响因子：
64.8
作者：
Fuchsberger, Christian;Flannick, Jason;Teslovich, Tanya M.;Mahajan, Anubha;Agarwala, Vineeta;Gaulton, Kyle J.;Ma, Clement;Fontanillas, Pierre;Moutsianas, Loukas;McCarthy, Davis J.;Rivas, Manuel A.;Perry, John R. B.;Sim, Xueling;Blackwell, Thomas W.;Robertson, Neil R.;Rayner, N. William;Cingolani, Pablo;Locke, Adam E.;Tajes, Juan Fernandez;Highland, Heather M.;Dupuis, Josee;Chines, Peter S.;Lindgren, Cecilia M.;Hartl, Christopher;Jackson, Anne U.;Chen, Han;Huyghe, Jeroen R.;van de Bunt, Martijn;Pearson, Richard D.;Kumar, Ashish;Mueller-Nurasyid, Martina;Grarup, Niels;Stringham, Heather M.;Gamazon, Eric R.;Lee, Jaehoon;Chen, Yuhui;Scott, Robert A.;Below, Jennifer E.;Chen, Peng;Huang, Jinyan;Go, Min Jin;Stitzel, Michael L.;Pasko, Dorota;Parker, Stephen C. J.;Varga, Tibor V.;Green, Todd;Beer, Nicola L.;Day-Williams, Aaron G.;Ferreira, Teresa;Fingerlin, Tasha;Horikoshi, Momoko;Hu, Cheng;Huh, Iksoo;Ikram, Mohammad Kamran;Kim, Bong-Jo;Kim, Yongkang;Kim, Young Jin;Kwon, Min-Seok;Lee, Juyoung;Lee, Selyeong;Lin, Keng-Han;Maxwell, Taylor J.;Nagai, Yoshihiko;Wang, Xu;Welch, Ryan P.;Yoon, Joon;Zhang, Weihua;Barzilai, Nir;Voight, Benjamin F.;Han, Bok-Ghee;Jenkinson, Christopher P.;Kuulasmaa, Teemu;Kuusisto, Johanna;Manning, Alisa;Ng, Maggie C. Y.;Palmer, Nicholette D.;Balkau, Beverley;Stancakova, Alena;Abboud, Hanna E.;Boeing, Heiner;Giedraitis, Vilmantas;Prabhakaran, Dorairaj;Gottesman, Omri;Scott, James;Carey, Jason;Kwan, Phoenix;Grant, George;Smith, Joshua D.;Neale, Benjamin M.;Purcell, Shaun;Butterworth, Adam S.;Howson, Joanna M. M.;Lee, Heung Man;Lu, Yingchang;Kwak, Soo-Heon;Zhao, Wei;Danesh, John;Lam, Vincent K. L.;Park, Kyong Soo;Saleheen, Danish;So, Wing Yee;Tam, Claudia H. T.;Afzal, Uzma;Aguilar, David;Arya, Rector;Aung, Tin;Chan, Edmund;Navarro, Carmen;Cheng, Ching-Yu;Palli, Domenico;Correa, Adolfo;Curran, Joanne E.;Rybin, Denis;Farook, Vidya S.;Fowler, Sharon P.;Freedman, Barry I.;Griswold, Michael;Hale, Daniel Esten;Hicks, Pamela J.;Khor, Chiea-Chuen;Kumar, Satish;Lehne, Benjamin;Thuillier, Dorothee;Lim, Wei Yen;Liu, Jianjun;van der Schouw, Yvonne T.;Loh, Marie;Musani, Solomon K.;Puppala, Sobha;Scott, William R.;Yengo, Loic;Tan, Sian-Tsung;Taylor, Herman A., Jr.;Thameem, Farook;Wilson, Gregory, Sr.;Wong, Tien Yin;Njolstad, Pal Rasmus;Levy, Jonathan C.;Mangino, Massimo;Bonnycastle, Lori L.;Schwarzmayr, Thomas;Fadista, Joao;Surdulescu, Gabriela L.;Herder, Christian;Groves, Christopher J.;Wieland, Thomas;Bork-Jensen, Jette;Brandslund, Ivan;Christensen, Cramer;Koistinen, Heikki A.;Doney, Alex S. F.;Kinnunen, Leena;Esko, Tonu;Farmer, Andrew J.;Hakaste, Liisa;Hodgkiss, Dylan;Kravic, Jasmina;Lyssenko, Valeriya;Hollensted, Mette;Jorgensen, Marit E.;Jorgensen, Torben;Ladenvall, Claes;Justesen, Johanne Marie;Karajamaki, Annemari;Kriebel, Jennifer;Rathmann, Wolfgang;Lannfelt, Lars;Lauritzen, Torsten;Narisu, Narisu;Linneberg, Allan;Melander, Olle;Milani, Lili;Neville, Matt;Orho-Melander, Marju;Qi, Lu;Qi, Qibin;Roden, Michael;Rolandsson, Olov;Swift, Amy;Rosengren, Anders H.;Stirrups, Kathleen;Wood, Andrew R.;Mihailov, Evelin;Blancher, Christine;Carneiro, Mauricio O.;Maguire, Jared;Poplin, Ryan;Shakir, Khalid;Fennell, Timothy;DePristo, Mark;de Angelis, Martin Hrabe;Deloukas, Panos;Gjesing, Anette P.;Jun, Goo;Nilsson, Peter;Murphy, Jacquelyn;Onofrio, Robert;Thorand, Barbara;Hansen, Torben;Meisinger, Christa;Hu, Frank B.;Isomaa, Bo;Karpe, Fredrik;Liang, Liming;Peters, Annette;Huth, Cornelia;O'Rahilly, Stephen P.;Palmer, Colin N. A.;Pedersen, Oluf;Rauramaa, Rainer;Tuomilehto, Jaakko;Salomaa, Veikko;Watanabe, Richard M.;Syvanen, Ann-Christine;Bergman, Richard N.;Bharadwaj, Dwaipayan;Bottinger, Erwin P.;Cho, Yoon Shin;Chandak, Giriraj R.;Chan, Juliana C. N.;Chia, Kee Seng;Daly, Mark J.;Ebrahim, Shah B.;Langenberg, Claudia;Elliott, Paul;Jablonski, Kathleen A.;Lehman, Donna M.;Jia, Weiping;Ma, Ronald C. W.;Pollin, Toni I.;Sandhu, Manjinder;Tandon, Nikhil;Froguel, Philippe;Barroso, Ines;Teo, Yik Ying;Zeggini, Eleftheria;Loos, Ruth J. F.;Small, Kerrin S.;Ried, Janina S.;DeFronzo, Ralph A.;Grallert, Harald;Glaser, Benjamin;Metspalu, Andres;Wareham, Nicholas J.;Walker, Mark;Banks, Eric;Gieger, Christian;Ingelsson, Erik;Im, Hae Kyung;Illig, Thomas;Franks, Paul W.;Buck, Gemma;Trakalo, Joseph;Buck, David;Prokopenko, Inga;Magi, Reedik;Lind, Lars;Farjoun, Yossi;Owen, Katharine R.;Gloyn, Anna L.;Strauch, Konstantin;Tuomi, Tiinamaija;Kooner, Jaspal Singh;Lee, Jong-Young;Park, Taesung;Donnelly, Peter;Morris, Andrew D.;Hattersley, Andrew T.;Bowden, Donald W.;Collins, Francis S.;Atzmon, Gil;Chambers, John C.;Spector, Timothy D.;Laakso, Markku;Strom, Tim M.;Bell, Graeme I.;Blangero, John;Duggirala, Ravindranath;Tai, E. Shyong;McVean, Gilean;Hanis, Craig L.;Wilson, James G.;Seielstad, Mark;Frayling, Timothy M.;Meigs, James B.;Cox, Nancy J.;Sladek, Rob;Lander, Eric S.;Gabriel, Stacey;Burtt, Noel P.;Mohlke, Karen L.;Meitinger, Thomas;Groop, Leif;Abecasis, Goncalo;Florez, Jose C.;Scott, Laura J.;Morris, Andrew P.;Kang, Hyun Min;Boehnke, Michael;Altshuler, David;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
8.2
作者：
Langenberg, C.;Sharp, S.;Forouhi, N. G.;Franks, P. W.;Schulze, M. B.;Kerrison, N.;Ekelund, U.;Barroso, I.;Panico, S.;Tormo, M. J.;Spranger, J.;Griffin, S.;van der Schouw, Y. T.;Amiano, P.;Ardanaz, E.;Arriola, L.;Balkau, B.;Barricarte, A.;Beulens, J. W. J.;Boeing, H.;Bueno-de-Mesquita, H. B.;Buijsse, B.;Chirlaque Lopez, M. D.;Clavel-Chapelon, F.;Crowe, F. L.;de Lauzon-Guillan, B.;Deloukas, P.;Dorronsoro, M.;Drogan, D.;Froguel, P.;Gonzalez, C.;Grioni, S.;Groop, L.;Groves, C.;Hainaut, P.;Halkjaer, J.;Hallmans, G.;Hansen, T.;Huerta Castano, J. M.;Kaaks, R.;Key, T. J.;Khaw, K. T.;Koulman, A.;Mattiello, A.;Navarro, C.;Nilsson, P.;Norat, T.;Overvad, K.;Palla, L.;Palli, D.;Pedersen, O.;Peeters, P. H.;Quiros, J. R.;Ramachandran, A.;Rodriguez-Suarez, L.;Rolandsson, O.;Romaguera, D.;Romieu, I.;Sacerdote, C.;Sanchez, M. J.;Sandbaek, A.;Slimani, N.;Sluijs, I.;Spijkerman, A. M. W.;Teucher, B.;Tjonneland, A.;Tumino, R.;van der A, D. L.;Verschuren, W. M. M.;Tuomilehto, J.;Feskens, E.;McCarthy, M.;Riboli, E.;Wareham, N. J.
通讯作者：
Wareham, N. J.
影响因子：
64.8
作者：
Murphy, Kevin G.;Bloom, Stephen R.
通讯作者：
Bloom, Stephen R.
影响因子：
30.8
作者：
Bonnefond, Amelie;Clement, Nathalie;Fawcett, Katherine;Yengo, Loic;Vaillant, Emmanuel;Guillaume, Jean-Luc;Dechaume, Aurelie;Payne, Felicity;Roussel, Ronan;Czernichow, Sebastien;Hercberg, Serge;Hadjadj, Samy;Balkau, Beverley;Marre, Michel;Lantieri, Olivier;Langenberg, Claudia;Bouatia-Naji, Nabila;Charpentier, Guillaume;Vaxillaire, Martine;Rocheleau, Ghislain;Wareham, Nicholas J.;Sladek, Robert;McCarthy, Mark I.;Dina, Christian;Barroso, Ines;Jockers, Ralf;Froguel, Philippe
通讯作者：
Froguel, Philippe