Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

被引：1379

作者：

Voight, Benjamin F. ^{[1
,2
,4
]}

Scott, Laura J. ^{[5
]}

Steinthorsdottir, Valgerdur ^{[6
]}

Morris, Andrew P. ^{[7
]}

Dina, Christian ^{[8
,9
,10
]}

Welch, Ryan P. ^{[11
]}

Zeggini, Eleftheria ^{[7
,12
]}

Huth, Cornelia ^{[13
,14
]}

Aulchenko, Yurii S. ^{[15
]}

Thorleifsson, Gudmar ^{[6
]}

McCulloch, Laura J. ^{[16
]}

Ferreira, Teresa ^{[7
]}

Grallert, Harald ^{[13
,14
]}

Amin, Najaf ^{[15
]}

Wu, Guanming ^{[17
]}

Willer, Cristen J. ^{[5
]}

Raychaudhuri, Soumya ^{[1
,2
,3
,18
]}

McCarroll, Steve A. ^{[1
,2
,18
]}

Langenberg, Claudia ^{[19
]}

Hofmann, Oliver M. ^{[20
]}

Dupuis, Josee ^{[21
,22
]}

Qi, Lu ^{[23
,24
,25
]}

Segre, Ayellet V. ^{[1
,2
,3
,18
]}

van Hoek, Mandy ^{[26
]}

Navarro, Pau ^{[27
]}

Ardlie, Kristin ^{[1
,2
]}

Balkau, Beverley ^{[28
,29
]}

Benediktsson, Rafn ^{[30
,31
]}

Bennett, Amanda J. ^{[16
]}

Blagieva, Roza ^{[32
]}

Boerwinkle, Eric ^{[33
,34
]}

Bonnycastle, Lori L. ^{[35
]}

Bostrom, Kristina Bengtsson ^{[36
]}

Bravenboer, Bert ^{[37
]}

Bumpstead, Suzannah ^{[12
]}

Burtt, Noisel P. ^{[1
,2
]}

Charpentier, Guillaume ^{[38
]}

Chines, Peter S. ^{[35
]}

Cornelis, Marilyn ^{[25
]}

Couper, David J. ^{[39
,40
]}

Crawford, Gabe ^{[1
,2
]}

Doney, Alex S. F. ^{[41
,42
]}

Elliott, Katherine S. ^{[7
]}

Elliott, Amanda L. ^{[1
,2
,18
,43
]}

Erdos, Michael R. ^{[35
]}

Fox, Caroline S. ^{[22
,44
]}

Franklin, Christopher S. ^{[45
]}

Ganser, Martha ^{[5
]}

Gieger, Christian ^{[13
]}

Grarup, Niels ^{[46
]}

机构：

[1] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA

[2] MIT, Cambridge, MA 02139 USA

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

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

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

[6] deCODE Genet, Reykjavik, Iceland

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

[8] CNRS, UMR 8090, Inst Biol, Lille, France

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

[10] CNRS, UMR915, INSERM, ERL3147, Nantes, France

[11] Univ Michigan, Bioinformat Program, Ann Arbor, MI 48109 USA

[12] Wellcome Trust Sanger Inst, Hinxton, England

[13] Helmholtz Zentrum Muenchen, Inst Epidemiol, Neuherberg, Germany

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

[15] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

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

[17] Ontario Inst Canc Res, Toronto, ON, Canada

[18] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02115 USA

[19] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England

[20] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

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

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

[23] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[24] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

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

[26] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[27] Western Gen Hosp, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[28] CESP Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Villejuif, France

[29] Univ Paris 11, UMRS 1018, Villejuif, France

[30] Landspitali Univ Hosp, Reykjavik, Iceland

[31] Iceland Heart Assoc, Kopavogur, Iceland

[32] Univ Ulm, Div Endocrinol Diabet & Metab, Ulm, Germany

[33] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA

[34] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA

[35] NHGRI, NIH, Bethesda, MD 20892 USA

[36] Skaraborg Primary Care, Ctr Res & Dev, Skovde, Sweden

[37] Catharina Hosp, Dept Internal Med, Eindhoven, Netherlands

[38] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France

[39] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[40] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA

[41] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland

[42] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogenom Ctr, Dundee, Scotland

[43] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[44] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

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

[46] Hagedorn Res Inst, Gentofte, Denmark

[47] Univ Poitiers, INSERM, U927, Ctr Hosp Univ Poitiers,UFR,CIC INSERM 0801, Poitiers, France

[48] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany

[49] Folkhalsan Res Ctr, Helsinki, Finland

[50] Malmska Municipal Hlth Ctr & Hosp, Pietarsaari, Finland

来源：

NATURE GENETICS | 2010年 / 42卷 / 07期

关键词：

GENOME-WIDE ASSOCIATION; FASTING PLASMA-GLUCOSE; QT INTERVAL DURATION; C-REACTIVE PROTEIN; COMMON VARIANTS; INSULIN-RESISTANCE; GENE-EXPRESSION; HNF1-ALPHA GENE; RISK LOCI; TRANSCRIPTION;

D O I：

10.1038/ng.609

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P < 5 x 10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

引用

页码：579 / U155

页数：13

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