Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hundreds of variants clustered in genomic loci and biological pathways affect human height.
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大多数常见的人类性状和疾病具有多基因遗传模式：许多遗传位点的DNA序列变异影响表型。全基因组关联（GWA）研究已经确定了超过600个与人类性状相关的变异，但这些通常解释了一小部分表型变异，这引发了对进一步研究效用的质疑。在这里，使用183，727个个体，我们表明至少180个基因座中的数百个遗传变异影响成年身高，这是一种高度遗传和经典的多基因性状。大量的基因座揭示了模式与人类常见疾病和性状的遗传研究的重要意义。首先，这180个位点不是随机的，而是富集了在生物学途径中连接的基因（P=0.016），以及构成骨骼生长缺陷的基础的基因（P<0.001）。第二，可能的致病基因通常位于最强相关的变异附近：在21个含有已知骨骼生长基因的基因座中，有13个基因最接近相关变异。第三，至少有19个基因座有多个独立相关的变异，这表明等位基因异质性是多基因性状的常见特征，对已经发现的基因座进行全面探索应该会发现更多的变异，并且可能已经确定了相当一部分相关基因座。第四，相关的变体富集了对基因的可能功能影响，在改变蛋白质的氨基酸结构和附近基因的表达水平的变体中过度呈现。我们的数据解释了身高表型变异的10%，我们估计，类似效应大小的未识别的常见变异将使这一数字增加到表型变异的16%（可遗传变异的20%）。虽然需要额外的方法来充分剖析多基因人类性状的遗传结构，但我们的研究结果表明，GWA研究可以识别大量涉及生物相关基因和途径的基因座。
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence phenotype. Genome-wide association (GWA) studies have identified >600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the utility of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P=0.016), and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants, and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented amongst variants that alter amino acid structure of proteins and expression levels of nearby genes. Our data explain ∼10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to ∼16% of phenotypic variation (∼20% of heritable variation). Although additional approaches are needed to fully dissect the genetic architecture of polygenic human traits, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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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：
158.5
作者：
Kofoed, EM;Hwa, V;Rosenfeld, RG
通讯作者：
Rosenfeld, RG
稀有变体会产生整个基因组的关联。
影响因子：
9.8
作者：
Dickson SP;Wang K;Krantz I;Hakonarson H;Goldstein DB
通讯作者：
Goldstein DB
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.
影响因子：
3.5
作者：
Estrada K;Krawczak M;Schreiber S;van Duijn K;Stolk L;van Meurs JB;Liu F;Penninx BW;Smit JH;Vogelzangs N;Hottenga JJ;Willemsen G;de Geus EJ;Lorentzon M;von Eller-Eberstein H;Lips P;Schoor N;Pop V;de Keijzer J;Hofman A;Aulchenko YS;Oostra BA;Ohlsson C;Boomsma DI;Uitterlinden AG;van Duijn CM;Rivadeneira F;Kayser M
通讯作者：
Kayser M