Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

被引：639

作者：

Scott, Robert A. ^{[2
]}

Lagou, Vasiliki ^{[3
,4
]}

Welch, Ryan P. ^{[5
,6
,7
]}

Wheeler, Eleanor ^{[8
]}

Montasser, May E. ^{[9
]}

Luan, Jian'an ^{[2
]}

Maegi, Reedik ^{[3
,10
]}

Strawbridge, Rona J. ^{[11
,12
]}

Rehnberg, Emil ^{[13
]}

Gustafsson, Stefan ^{[13
]}

Kanoni, Stavroula ^{[8
]}

Rasmussen-Torvik, Laura J. ^{[14
]}

Yengo, Loic ^{[15
,16
]}

Lecoeur, Cecile ^{[15
,16
]}

Shungin, Dmitry ^{[17
,18
,19
]}

Sanna, Serena ^{[20
]}

Sidore, Carlo ^{[6
,7
,20
,21
]}

Johnson, Paul C. D. ^{[22
]}

Jukema, J. Wouter ^{[23
,24
]}

Johnson, Toby ^{[25
,26
]}

Mahajan, Anubha ^{[3
]}

Verweij, Niek ^{[27
]}

Thorleifsson, Gudmar ^{[28
]}

Hottenga, Jouke-Jan ^{[29
,30
]}

Shah, Sonia ^{[31
]}

Smith, Albert V. ^{[32
,33
]}

Sennblad, Bengt ^{[11
]}

Gieger, Christian ^{[34
]}

Salo, Perttu ^{[35
]}

Perola, Markus ^{[10
,35
,36
]}

Timpson, Nicholas J. ^{[37
]}

Evans, David M. ^{[37
]}

St Pourcain, Beate

Wu, Ying ^{[38
]}

Andrews, Jeanette S. ^{[39
]}

Hui, Jennie ^{[40
,41
,42
,43
]}

Bielak, Lawrence F. ^{[44
]}

Zhao, Wei ^{[44
]}

Horikoshi, Momoko ^{[3
,4
]}

Navarro, Pau ^{[45
]}

Isaacs, Aaron ^{[46
,47
]}

O'Connell, Jeffrey R. ^{[9
]}

Stirrups, Kathleen ^{[8
]}

Vitart, Veronique ^{[45
]}

Hayward, Caroline ^{[45
]}

Esko, Tonu ^{[10
,48
]}

Mihailov, Evelin ^{[48
]}

Fraser, Ross M. ^{[49
]}

Fall, Tove ^{[13
]}

Voight, Benjamin F. ^{[50
,51
]}

机构：

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

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

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

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

[5] Univ Michigan, Sch Med, Bioinformat Grad Program, Ann Arbor, MI USA

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

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

[8] Wellcome Trust Sanger Inst, Cambridge, England

[9] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

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

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

[12] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden

[13] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[14] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA

[15] Univ Lille Nord France, Lille, France

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

[17] Lund Univ, Dept Clin Sci, Skane Univ Hosp Malmo, Genet & Mol Epidemiol Unit, Malmo, Sweden

[18] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden

[19] Umea Univ, Dept Odontol, Umea, Sweden

[20] CNR, Ist Ric Genet & Biomed, Monserrato, Italy

[21] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy

[22] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland

[23] Durrer Ctr Cardiogenet Res, ICIN, Utrecht, Netherlands

[24] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands

[25] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Dept Clin Pharmacol, London, England

[26] Queen Mary Univ London, Barts & London Sch Med & Dent, Genome Ctr, London, England

[27] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[28] deCODE Genet, Rekjavik, Iceland

[29] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[30] EMGO Inst, Amsterdam, Netherlands

[31] UCL, Univ Coll London Genet Inst UGI, London, England

[32] Iceland Heart Assoc, Kopavogur, Iceland

[33] Univ Iceland, Fac Med, Reykjavik, Iceland

[34] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany

[35] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[36] Univ Helsinki, Inst Mol Med, Finland FIMM, Helsinki, Finland

[37] Univ Bristol, Sch Social & Community Med, MRC Council Ctr Causal Anal Translat Epidemiol CA, Bristol, Avon, England

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

[39] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA

[40] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia

[41] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia

[42] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia

[43] PathW Lab Med WA, Nedlands, WA, Australia

[44] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[45] Univ Edinburgh, Western Gen Hosp, Med Res Council Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[46] CMSB, Leiden, Netherlands

[47] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands

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

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

[50] Broad Inst Harvard & MIT, Boston, MA USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 09期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; KLOTHO GENE POLYMORPHISMS; BINDING-PROTEIN-ALPHA; INSULIN-RESISTANCE; GLUCOSE-METABOLISM; SUSCEPTIBILITY LOCI; KAPPA-B; CARDIOVASCULAR-DISEASE; SKELETAL-MUSCLE;

D O I：

10.1038/ng.2385

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

引用

页码：991 / +

页数：18

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