Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

被引：1433

作者：

Morris, Andrew P. ^{[1
]}

Voight, Benjamin F. ^{[2
,3
]}

Teslovich, Tanya M. ^{[4
]}

Ferreira, Teresa ^{[1
]}

Segre, Ayellet V. ^{[2
,5
,6
]}

Steinthorsdottir, Valgerdur ^{[7
]}

Strawbridge, Rona J. ^{[8
,9
]}

Khan, Hassan ^{[10
]}

Grallert, Harald ^{[11
]}

Mahajan, Anubha ^{[1
]}

Prokopenko, Inga ^{[1
,12
]}

Kang, Hyun Min ^{[4
]}

Dina, Christian ^{[13
,14
,15
]}

Esko, Tonu ^{[16
,17
]}

Fraser, Ross M. ^{[18
]}

Kanoni, Stavroula ^{[19
]}

Kumar, Ashish ^{[1
]}

Lagou, Vasiliki ^{[1
]}

Langenberg, Claudia ^{[20
]}

Luan, Jian'an ^{[20
]}

Lindgren, Cecilia M. ^{[1
]}

Mueller-Nurasyid, Martina ^{[21
,22
,23
]}

Pechlivanis, Sonali ^{[24
]}

Rayner, N. William ^{[1
,12
]}

Scott, Laura J. ^{[4
]}

Wiltshire, Steven ^{[1
]}

Yengo, Loic ^{[25
,26
,27
]}

Kinnunen, Leena ^{[28
]}

Rossin, Elizabeth J. ^{[2
,5
,29
,30
,31
]}

Raychaudhuri, Soumya ^{[2
,32
,33
]}

Johnson, Andrew D. ^{[34
]}

Dimas, Antigone S. ^{[1
,35
,36
]}

Loos, Ruth J. F. ^{[20
,37
,38
,39
]}

Vedantam, Sailaja ^{[40
,41
]}

Chen, Han ^{[42
]}

Florez, Jose C. ^{[5
,6
,40
,43
]}

Fox, Caroline ^{[34
,44
]}

Liu, Ching-Ti ^{[42
]}

Rybin, Denis ^{[45
]}

Couper, David J. ^{[46
]}

Kao, Wen Hong L. ^{[47
]}

Li, Man ^{[47
]}

Cornelis, Marilyn C. ^{[48
]}

Kraft, Peter ^{[48
,49
]}

Sun, Qi ^{[48
,50
]}

van Dam, Rob M. ^{[48
,51
]}

Stringham, Heather M. ^{[4
]}

Chines, Peter S. ^{[52
]}

Fischer, Krista ^{[16
]}

Fontanillas, Pierre ^{[2
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA

[3] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

[4] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[5] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[6] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[7] deCODE Genet, Reykjavik, Iceland

[8] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden

[9] Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden

[10] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[11] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[12] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[13] INSERM, UMR 1087, Nantes, France

[14] CNRS, UMR 6291, Nantes, France

[15] Univ Nantes, Dept Biol Med & Hlth, Nantes, France

[16] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[17] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[18] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[19] Wellcome Trust Sanger Inst, Cambridge, England

[20] Addenbrookes Hosp, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England

[21] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[22] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany

[23] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany

[24] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany

[25] Inst Pasteur, CNRS, UMR 8199, Inst Biol, F-59019 Lille, France

[26] Univ Lille 2, Inst Pasteur, Lille, France

[27] Univ Lille 1, Model Data Anal & Learning MODAL Team, Inst Natl Rech Informat & Automat INRIA Lille Nor, Math Lab,CNRS,UMR 8524, Lille, France

[28] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland

[29] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA

[30] MIT, Boston, MA USA

[31] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA

[32] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

[33] Partners Ctr Personalized Genom Med, Boston, MA USA

[34] NHLBI, Framingham Heart Study, Framingham, MA USA

[35] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[36] Biomed Sci Res Ctr Al Fleming, Vari, Greece

[37] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA

[38] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA

[39] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA

[40] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[41] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA

[42] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[43] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA

[44] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA

[45] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA

[46] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA

[47] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[48] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA

[49] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA

[50] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 09期

基金：

英国惠康基金; 芬兰科学院; 瑞典研究理事会; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COMMON VARIANTS; METAANALYSIS; EXPRESSION; RISK; INDIVIDUALS; REPLICATION; GLUCOSE; MC4R;

D O I：

10.1038/ng.2383

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genomewide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

引用

页码：981 / +

页数：12

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