Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

被引：149

作者：

Wessel, Jennifer ^{[1
,2
]}

Chu, Audrey Y. ^{[3
,4
]}

Willems, Sara M. ^{[5
,6
]}

Wang, Shuai ^{[7
]}

Yaghootkar, Hanieh ^{[8
]}

Brody, Jennifer A. ^{[9
,10
]}

Dauriz, Marco ^{[11
,12
,13
,14
]}

Hivert, Marie-France ^{[15
,16
,17
]}

Raghavan, Sridharan ^{[11
,12
]}

Lipovich, Leonard ^{[18
,19
]}

Hidalgo, Bertha ^{[20
]}

Fox, Keolu ^{[10
,21
]}

Huffman, Jennifer E. ^{[4
,22
]}

An, Ping ^{[23
]}

Lu, Yingchang ^{[24
,25
]}

Rasmussen-Torvik, Laura J. ^{[26
]}

Grarup, Niels ^{[27
]}

Ehm, Margaret G.

Li, Li

Baldridge, Abigail S. ^{[26
]}

Stancakova, Alena ^{[28
]}

Abrol, Ravinder ^{[29
,30
,31
]}

Besse, Celine ^{[32
]}

Boland, Anne ^{[32
]}

Bork-Jensen, Jette ^{[27
]}

Fornage, Myriam ^{[33
]}

Freitag, Daniel F. ^{[34
,35
]}

Garcia, Melissa E. ^{[36
]}

Guo, Xiuqing ^{[37
]}

Hara, Kazuo ^{[24
,25
]}

Isaacs, Aaron ^{[5
,24
,118
]}

Jakobsdottir, Johanna ^{[38
]}

Lange, Leslie A. ^{[39
]}

Layton, Jill C. ^{[40
]}

Li, Man ^{[41
]}

Zhao, Jing Hua ^{[6
]}

Meidtner, Karina ^{[42
]}

Morrison, Alanna C. ^{[43
]}

Nalls, Mike A. ^{[44
]}

Peters, Marjolein J. ^{[45
,46
]}

Sabater-Lleal, Maria ^{[47
]}

Schurmann, Claudia ^{[24
,25
]}

Silveira, Angela ^{[47
]}

Smith, Albert V. ^{[38
,48
]}

Southam, Lorraine ^{[34
,49
]}

Stoiber, Marcus H. ^{[50
]}

Strawbridge, Rona J. ^{[47
]}

Taylor, Kent D. ^{[37
]}

Varga, Tibor V. ^{[51
]}

Allin, Kristine H. ^{[27
]}

机构：

[1] Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA

[3] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA

[4] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA

[5] Erasmus Univ, Ctr Med, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CE Rotterdam, Netherlands

[6] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0SL, England

[7] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[8] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England

[9] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA

[10] Univ Washington, Dept Med, Seattle, WA 98195 USA

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

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

[13] Univ Verona, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, I-37126 Verona, Italy

[14] Hosp Trust Verona, I-37126 Verona, Italy

[15] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA

[16] Univ Sherbrooke, Dept Med, Div Endocrinol & Metab, Sherbrooke, PQ J1K 2R1, Canada

[17] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA

[18] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA

[19] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48202 USA

[20] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA

[21] Univ Washington, Dept Gen Sci, Seattle, WA 98195 USA

[22] Univ Edinburgh, MRC IGMM, MRC Human Genet, Edinburgh EH4 2XU, Midlothian, Scotland

[23] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA

[24] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[25] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

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

[27] Univ Copenhagen, Fac Med & Hlth Sci, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark

[28] Univ Eastern Finland, Inst Clin Med, FI-70211 Kuopio, Finland

[29] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA

[30] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA

[31] CALTECH, Mat & Proc Simulat Ctr, Pasadena, CA 91125 USA

[32] CEA, Ctr Natl Genotypage, Inst Genom, F-91057 Evry, France

[33] Univ Texas Houston, Hlth Sci Ctr, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[34] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[35] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England

[36] Natl Inst Aging, Intramural Res Program, Bethesda, MD 21224 USA

[37] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA

[38] Iceland Heart Assoc, IS-201 Kopavogur, Iceland

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

[40] Indiana Univ, Fairbanks Sch Publ Hlth, Indianapolis, IN 46202 USA

[41] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA

[42] German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, DE-14558 Nuthetal, Germany

[43] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77225 USA

[44] NIA, Neurogenet Lab, Bethesda, MD 20892 USA

[45] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 Rotterdam, Netherlands

[46] NGI NCHA, NL-2300 RC Leiden, Netherlands

[47] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, S-17177 Stockholm, Sweden

[48] Univ Iceland, IS-101 Reykjavik, Iceland

[49] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[50] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Genome Dynam, Berkeley, CA 94720 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

英国医学研究理事会; 瑞典研究理事会; 英国惠康基金; 美国国家卫生研究院; 瑞士国家科学基金会; 芬兰科学院; 欧洲研究理事会; 美国国家环境保护局; 俄罗斯基础研究基金会;

关键词：

GLUCAGON-LIKE PEPTIDE-1; GERMLINE MUTATIONS; CODING VARIATION; GLYCEMIC TRAITS; PLASMA-GLUCOSE; P446L VARIANT; RECEPTOR GENE; LOCI; PROTEIN; TRIGLYCERIDE;

D O I：

10.1038/ncomms6897

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

引用

页数：16

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