A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

被引：511

作者：

Manning, Alisa K. ^{[2
,3
,4
,5
]}

Hivert, Marie-France ^{[1
,6
]}

Scott, Robert A. ^{[7
]}

Grimsby, Jonna L. ^{[1
,8
]}

Bouatia-Naji, Nabila ^{[9
,10
]}

Chen, Han ^{[2
]}

Rybin, Denis ^{[11
]}

Liu, Ching-Ti ^{[2
]}

Bielak, Lawrence F. ^{[12
]}

Prokopenko, Inga ^{[13
,14
]}

Amin, Najaf ^{[15
]}

Barnes, Daniel ^{[7
]}

Cadby, Gemma ^{[16
,17
]}

Hottenga, Jouke-Jan ^{[18
]}

Ingelsson, Erik ^{[19
]}

Jackson, Anne U. ^{[20
,21
]}

Johnson, Toby ^{[22
]}

Kanoni, Stavroula

Ladenvall, Claes ^{[24
,25
]}

Lagou, Vasiliki ^{[13
,14
]}

Lahti, Jari ^{[26
]}

Lecoeur, Cecile ^{[9
,10
]}

Liu, Yongmei ^{[27
]}

Martinez-Larrad, Maria Teresa ^{[28
]}

Montasser, May E. ^{[29
]}

Navarro, Pau ^{[30
]}

Perry, John R. B. ^{[14
,31
,32
]}

Rasmussen-Torvik, Laura J. ^{[33
]}

Salo, Perttu

Sattar, Naveed ^{[35
]}

Shungin, Dmitry ^{[24
,25
,36
,37
]}

Strawbridge, Rona J. ^{[38
]}

Tanaka, Toshiko

van Duijn, Cornelia M. ^{[15
,40
,41
]}

An, Ping ^{[42
]}

de Andrade, Mariza ^{[43
]}

Andrews, Jeanette S. ^{[44
]}

Aspelund, Thor ^{[45
,46
]}

Atalay, Mustafa ^{[47
]}

Aulchenko, Yurii ^{[15
]}

Balkau, Beverley ^{[48
,49
]}

Bandinelli, Stefania ^{[50
]}

Beckmann, Jacques S. ^{[51
,52
]}

Beilby, John P. ^{[53
,54
,55
]}

Bellis, Claire ^{[56
]}

Bergman, Richard N. ^{[57
]}

Blangero, John ^{[56
]}

Boban, Mladen ^{[58
]}

Boehnke, Michael ^{[20
,21
]}

Boerwinkle, Eric ^{[59
]}

机构：

[1] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA

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

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

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

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

[6] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1K 2R1, Canada

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

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

[9] Inst Pasteur, Lille, France

[10] Univ Lille Nord France, Lille, France

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

[12] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

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

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

[15] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

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

[17] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada

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

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

[20] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA

[21] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[22] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol & Genome Ctr, London, England

[23] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge, England

[24] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[25] Lund Univ, Ctr Diabet, Malmo, Sweden

[26] Univ Helsinki, Inst Behav Sci, Helsinki, Finland

[27] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA

[28] Inst Invest Sanitaria Hosp Clin San Carlos, Spanish Biomed Res Ctr Diabet & Associated Metab, Madrid, Spain

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

[30] Univ Edinburgh, MRC Human Genet Unit, MRC Inst Genet & Mol Med IGMM, Edinburgh, Midlothian, Scotland

[31] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

[32] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

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

[34] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Diabet Prevent Unit, Helsinki, Finland

[35] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[36] Umea Univ Hosp, Genet Epidemiol & Clin Res Grp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden

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

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

[39] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA

[40] Netherlands Genom Initiat, Ctr Med Syst Biol, The Hague, Netherlands

[41] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, Rotterdam, Netherlands

[42] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[43] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

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

[45] Iceland Heart Assoc, Kopavogur, Iceland

[46] Univ Iceland, Reykjavik, Iceland

[47] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland

[48] INSERM, Ctr Res Epidemiol & Populat Hlth, Ctr Rech Epidemiol & Sante Populat CESP, Villejuif, France

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

[50] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy

来源：

NATURE GENETICS | 2012年 / 44卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

ENVIRONMENT INTERACTION; ASSOCIATION ANALYSIS; COMMON VARIANTS; LOCI; SUSCEPTIBILITY; RISK; POLYMORPHISM; TANKYRASE; RECEPTOR; GLUCOSE;

D O I：

10.1038/ng.2274

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

引用

页码：659 / U81

页数：13

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