Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

被引：69

作者：

Horikoshi, Momoko ^{[1
,2
]}

Maegi, Reedik ^{[3
]}

van de Bunt, Martijn ^{[1
,2
]}

Surakka, Ida ^{[4
,5
]}

Sarin, Antti-Pekka ^{[4
,5
]}

Mahajan, Anubha ^{[1
]}

Marullo, Letizia ^{[6
]}

Thorleifsson, Gudmar ^{[7
]}

Haegg, Sara ^{[8
,9
]}

Hottenga, Jouke-Jan ^{[10
]}

Ladenvall, Claes ^{[11
]}

Ried, Janina S. ^{[12
]}

Winkler, Thomas W. ^{[13
]}

Willems, Sara M. ^{[14
]}

Pervjakova, Natalia ^{[3
]}

Esko, Tonu ^{[3
,15
,16
,17
,18
]}

Beekman, Marian ^{[19
,20
]}

Nelson, Christopher P. ^{[21
,22
]}

Willenborg, Christina ^{[23
,24
]}

Wiltshire, Steven ^{[1
,2
]}

Ferreira, Teresa ^{[1
]}

Fernandez, Juan ^{[1
]}

Gaulton, Kyle J. ^{[1
]}

Steinthorsdottir, Valgerdur ^{[7
]}

Hamsten, Anders ^{[25
]}

Magnusson, Patrik K. E. ^{[8
]}

Willemsen, Gonneke ^{[10
]}

Milaneschi, Yuri ^{[26
]}

Robertson, Neil R. ^{[1
,2
]}

Groves, Christopher J. ^{[2
]}

Bennett, Amanda J. ^{[2
]}

Lehtimaeki, Terho ^{[27
,28
]}

Viikari, Jorma S. ^{[29
,30
]}

Rung, Johan ^{[31
]}

Lyssenko, Valeriya ^{[11
,32
]}

Perola, Markus ^{[4
,5
]}

Heid, Iris M. ^{[13
]}

Herder, Christian ^{[33
,34
]}

Grallert, Harald ^{[35
,36
]}

Mueller-Nurasyid, Martina ^{[12
,37
,38
]}

Roden, Michael ^{[33
,34
,39
]}

Hypponen, Elina ^{[40
,41
]}

Isaacs, Aaron ^{[14
,42
]}

van Leeuwen, Elisabeth M. ^{[14
]}

Karssen, Lennart C. ^{[14
]}

Mihailov, Evelin ^{[3
]}

Houwing-Duistermaat, Jeanine J. ^{[43
]}

de Craen, Anton J. M. ^{[20
,44
]}

Deelen, Joris ^{[19
,20
]}

Havulinna, Aki S. ^{[45
]}

机构：

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

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

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

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

[5] Natl Inst Hlth & Welf, Helsinki, Finland

[6] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy

[7] deCode Genet Amgen Inc, Reykjavik, Iceland

[8] Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden

[9] Uppsala Univ, Dept Med Sci Mol Epidemiol & Sci, Life Lab, Uppsala, Sweden

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

[11] Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

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

[13] Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany

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

[15] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[16] Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA

[17] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

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

[19] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands

[20] Netherlands Consortium Hlth Ageing, Leiden, Netherlands

[21] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[22] Natl Inst Hlth Res, Leicester Cardiovasc Dis Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England

[23] Univ Lubeck, Inst Integrat & Expt Gen, Lubeck, Germany

[24] DZHK German Ctr Cardiovascular Res, Lubeck, Germany

[25] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Cardiovascular Genet & Genom Grp, Stockholm, Sweden

[26] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands

[27] Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland

[28] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland

[29] Univ Turku, Dept Med, Turku, Finland

[30] Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland

[31] European Bioinformat Inst, European Mol Biol Lab, Hinxton, England

[32] Steno Diabet Ctr AS, Gentofte, Denmark

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

[34] German Ctr Diabet Res DZD eV, Partner Dusseldorf, Dusseldorf, Germany

[35] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany

[36] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany

[37] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany

[38] Univ Munich, Inst Med Informat,Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany

[39] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany

[40] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5001, Australia

[41] UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England

[42] Ctr Med Syst Biol, Leiden, Netherlands

[43] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands

[44] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands

[45] Natl Inst Hlth & Welf, Unit Chron Dis Epidemiol & Prevent, Helsinki, Finland

[46] Univ Leicester, Bioinformat & Biostatist Support Hub, Leicester, Leics, England

[47] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany

[48] DZHK German Ctr Cardiovasc Res, Munich, Germany

[49] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[50] Univ Leicester, Dept Hlth Sci, Genet Epidemiol Grp, Leicester, Leics, England

来源：

PLOS GENETICS | 2015年 / 11卷 / 07期

基金：

英国惠康基金; 芬兰科学院; 瑞典研究理事会; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; WAIST-HIP RATIO; LOW-FREQUENCY; FASTING GLUCOSE; GENOTYPE IMPUTATION; INSULIN-RESISTANCE; PROVIDES INSIGHTS; GENETIC-VARIATION; CHROMATIN STATES;

D O I：

10.1371/journal.pgen.1005230

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency >= 0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

引用

页数：24

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