Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
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DOI：
10.1371/journal.pgen.1005230
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发表时间：
2015-07
期刊：
影响因子：
4.5
通讯作者：
ENGAGE Consortium
中科院分区：
文献类型：
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作者：
Horikoshi M;Mӓgi R;van de Bunt M;Surakka I;Sarin AP;Mahajan A;Marullo L;Thorleifsson G;Hӓgg S;Hottenga JJ;Ladenvall C;Ried JS;Winkler TW;Willems SM;Pervjakova N;Esko T;Beekman M;Nelson CP;Willenborg C;Wiltshire S;Ferreira T;Fernandez J;Gaulton KJ;Steinthorsdottir V;Hamsten A;Magnusson PK;Willemsen G;Milaneschi Y;Robertson NR;Groves CJ;Bennett AJ;Lehtimӓki T;Viikari JS;Rung J;Lyssenko V;Perola M;Heid IM;Herder C;Grallert H;Müller-Nurasyid M;Roden M;Hypponen E;Isaacs A;van Leeuwen EM;Karssen LC;Mihailov E;Houwing-Duistermaat JJ;de Craen AJ;Deelen J;Havulinna AS;Blades M;Hengstenberg C;Erdmann J;Schunkert H;Kaprio J;Tobin MD;Samani NJ;Lind L;Salomaa V;Lindgren CM;Slagboom PE;Metspalu A;van Duijn CM;Eriksson JG;Peters A;Gieger C;Jula A;Groop L;Raitakari OT;Power C;Penninx BW;de Geus E;Smit JH;Boomsma DI;Pedersen NL;Ingelsson E;Thorsteinsdottir U;Stefansson K;Ripatti S;Prokopenko I;McCarthy MI;Morris AP;ENGAGE Consortium
来自1000基因组（1000G）项目联盟的参考面板几乎完全覆盖了欧洲祖先人群中常见和低频的遗传变异，次要等位基因频率≥0.5%。在欧洲遗传和基因组流行病学网络（ENGAGE）联盟内，我们对全基因组关联研究（GWAS）进行了首次大规模荟萃分析，并辅以1000G代入，对多达87,048名欧洲血统的个体进行了四项定量血糖和肥胖相关特征的分析。我们确定了两个具有全基因组意义的体重指数（BMI）位点，以及两个与空腹血糖（FG）相关的位点，这些位点之前都没有在结合欧洲血统GWAS的大型荟萃分析中报道过。通过条件分析，我们还检测到多个不同的关联映射信号，这些信号与BMI调整后的腰臀比（RSPO3）和FG （GCK和G6PC2）建立的基因座相关。G6PC2位点上一个关联信号的索引变异是一个低频编码等位基因H177Y，最近被证明在葡萄糖调节中具有功能作用。精细定位分析显示，非编码变异体最有可能在已建立的和新的基因座上驱动关联信号，因为它们与增强子元件重叠而富集，对于FG来说，增强子元件被定位到胰岛的启动子和转录因子结合位点。我们的研究表明，GWAS基因座上常见和低频变异关联信号的1000G代入和遗传精细定位，结合相关组织的基因组注释，可以深入了解其对血糖和肥胖相关性状的影响的功能和调控机制。人类遗传学研究表明，定量的人体测量学和代谢特征，包括体重指数、腰臀比、血浆葡萄糖和胰岛素浓度，具有高度遗传性，是2型糖尿病和心血管疾病的确定危险因素。尽管基因组的许多区域都与这些特征有关，但具体的基因尚未被确定。通过使用先进的统计“归因”技术，应用于超过87,000个欧洲血统的个体，以及超过3700万个遗传变异的公开“参考面板”，我们已经能够识别与这些血糖和肥胖相关特征相关的基因组的新区域，并定位这些区域中最有可能是因果关系的基因。这提高了对血糖和肥胖相关特征的生物学机制的理解是非常重要的，因为它可以推进下游疾病终点的药物开发，最终带来公共卫生益处。
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. Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
30.8
作者：
通讯作者：
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
30.8
作者：
Chambers, John C.;Elliott, Paul;Kooner, Jaspal S.
通讯作者：
Kooner, Jaspal S.