Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

被引：1407

作者：

Zeggini, Eleftheria

Scott, Laura J. ^{[2
,3
]}

Saxena, Richa ^{[4
,5
,6
,7
,8
,9
,10
]}

Voight, Benjamin F. ^{[4
,5
,6
,7
,9
]}

Marchini, Jonathan L. ^{[1
,11
]}

Hu, Tianle ^{[2
]}

de Bakker, Paul I. W. ^{[5
,9
,12
]}

Abecasis, Goncalo R. ^{[7
]}

Almgren, Peter

Andersen, Gitte ^{[2
,3
,14
]}

Ardlie, Kristin ^{[4
,5
]}

Bostroem, Kristina Bengtsson ^{[2
,3
,15
]}

Bergman, Richard N. ^{[16
]}

Bonnycastle, Lori L. ^{[17
]}

Borch-Johnsen, Knut ^{[4
,14
,18
]}

Burtt, Noel P. ^{[4
]}

Chen, Hong ^{[19
]}

Chines, Peter S. ^{[13
,17
]}

Daly, Mark J. ^{[6
,7
,9
]}

Deodhar, Parimal ^{[4
,17
]}

Ding, Chia-Jen ^{[2
]}

Doney, Alex S. F. ^{[20
]}

Duren, William L. ^{[2
,3
,4
]}

Elliott, Katherine S. ^{[1
]}

Erdos, Michael R. ^{[2
,3
,17
]}

Frayling, Timothy M. ^{[21
,22
]}

Freathy, Rachel M. ^{[2
,21
,22
]}

Gianniny, Lauren ^{[4
]}

Grallert, Harald ^{[23
]}

Grarup, Niels ^{[14
]}

Groves, Christopher J. ^{[24
]}

Guiducci, Candace ^{[4
]}

Hansen, Torben ^{[14
]}

Herder, Christian ^{[25
]}

Hitman, Graham A. ^{[26
]}

Hughes, Thomas E. ^{[4
,19
]}

Isomaa, Bo ^{[27
,28
]}

Jackson, Anne U. ^{[2
,3
]}

Jorgensen, Torben ^{[29
]}

Kong, Augustine ^{[30
]}

Kubalanza, Kari ^{[17
]}

Kuruvilla, Finny G. ^{[4
,5
,8
]}

Kuusisto, Johanna ^{[31
,32
]}

Langenberg, Claudia ^{[33
]}

Lango, Hana ^{[21
,22
]}

Lauritzen, Torsten ^{[4
,34
]}

Li, Yun ^{[2
,3
]}

Lindgren, Cecilia M. ^{[1
,24
]}

Lyssenko, Valeriya ^{[13
]}

Marvelle, Amanda F. ^{[35
]}

机构：

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

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

[3] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[4] Broad Inst Harvard, Cambridge, MA 02142 USA

[5] MIT, Cambridge, MA 02142 USA

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

[7] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[8] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[11] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[12] Brigham & Womens Hosp, Harvard Partners Ctr Genet & Genom, Boston, MA 02115 USA

[13] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Res Unit, Malmo Univ Hosp, S-20502 Malmo, Sweden

[14] Steno Diabet Ctr, DK-2820 Copenhagen, Denmark

[15] Skaraborg Inst, S-54130 Skovde, Sweden

[16] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA

[17] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA

[18] Univ Aarhus, Fac Hlth Sci, DK-8000 Aarhus, Denmark

[19] Novartis Inst Biomed Res, Diabet & Metab Dis Area, Cambridge, MA 02139 USA

[20] Ninewells Hosp & Med Sch, Diabet Res Grp, Div Med & Therapeut, Dundee DD1 9SY, Scotland

[21] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England

[22] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England

[23] Gesell Strahlenforsch Natl Res Ctr Environm & Hlt, Inst Epidemiol, D-85764 Neuherberg, Germany

[24] Univ Oxford, Oxford Ctr Diabetes Endocrinol & Metab, Oxford OX3 7LJ, England

[25] Univ Dusseldorf, Inst Clin Diabet Res, German Diabetes Ctr, Leiden Inst, D-40225 Dusseldorf, Germany

[26] Royal London Hosp, Ctr Diabet & Metab Med, London E1 1BB, England

[27] Malmska Municipal Hlth Ctr & Hosp, FIN-68601 Pietarsaari, Finland

[28] Folkhalsan Res Ctr, FIN-00014 Helsinki, Finland

[29] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark

[30] deCODE Genet, IS-101 Reykjavik, Iceland

[31] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland

[32] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[33] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge CB2 0QQ, England

[34] Univ Aarhus, Dept Gen Practice, DK-8000 Aarhus, Denmark

[35] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[36] Norwegian Univ Sci & Technol, HUNT Res Ctr, Dept Publ Hlth & Gen Practice, Fac Med, N-7650 Verdal, Norway

[37] Ninewells Hosp & Med Sch, Populat Pharmacogenet Grp, Biomed Res Ctr, Dundee DD1 9SY, Scotland

[38] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge CB10 1SA, England

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

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

[41] Harvard Univ, Sch Med, Boston, MA 02115 USA

[42] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA

[43] Univ Bristol, MRC Ctr Causal Analyses Translat Epidemiol, Bristol BS2 8PR, Avon, England

[44] Univ Helsinki, Helsinki Univ Hosp, Dept Med, FIN-00300 Helsinki, Finland

[45] Natl Publ Hlth Inst, Diabet Unit, Dept Epidemiol & Hlth Promot, SF-00300 Helsinki, Finland

[46] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland

[47] S Ostrobothnia Cent Hosp, Seinajoki 60220, Finland

[48] Newcastle Univ, Diabet Res Grp, Sch Clin Med Sci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[49] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[50] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7600 Levanger, Norway

来源：

NATURE GENETICS | 2008年 / 40卷 / 05期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

D O I：

10.1038/ng.120

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

引用

页码：638 / 645

页数：8

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