Hundreds of variants clustered in genomic loci and biological pathways affect human height

被引：1457

作者：

Allen, Hana Lango ^{[1
]}

Estrada, Karol ^{[2
,3
,4
]}

Lettre, Guillaume ^{[5
,6
]}

Berndt, Sonja I. ^{[7
]}

Weedon, Michael N. ^{[1
]}

Rivadeneira, Fernando ^{[2
,3
,4
]}

Willer, Cristen J. ^{[8
]}

Jackson, Anne U. ^{[8
]}

Vedantam, Sailaja ^{[9
,10
,11
]}

Raychaudhuri, Soumya ^{[12
,13
,14
]}

Ferreira, Teresa ^{[15
]}

Wood, Andrew R. ^{[1
]}

Weyant, Robert J. ^{[8
]}

Segre, Ayellet V. ^{[12
,13
,16
,17
]}

Speliotes, Elizabeth K. ^{[18
]}

Wheeler, Eleanor ^{[19
]}

Soranzo, Nicole ^{[19
,20
]}

Park, Ju-Hyun ^{[7
]}

Yang, Jian ^{[21
]}

Gudbjartsson, Daniel ^{[22
]}

Heard-Costa, Nancy L. ^{[23
]}

Randall, Joshua C. ^{[15
]}

Qi, Lu ^{[24
,25
,26
]}

Smith, Albert Vernon ^{[27
,28
]}

Maegi, Reedik ^{[15
]}

Pastinen, Tomi ^{[29
,30
,31
]}

Liang, Liming ^{[32
,33
]}

Heid, Iris M. ^{[34
,35
]}

Luan, Jian'an ^{[36
]}

Thorleifsson, Gudmar ^{[22
]}

Winkler, Thomas W. ^{[34
]}

Goddard, Michael E. ^{[37
,38
]}

Lo, Ken Sin ^{[5
]}

Palmer, Cameron ^{[9
,10
,11
]}

Workalemahu, Tsegaselassie ^{[24
]}

Aulchenko, Yurii S. ^{[2
,4
]}

Johansson, Asa ^{[39
,40
]}

Zillikens, M. Carola ^{[3
]}

Feitosa, Mary F. ^{[41
]}

Esko, Tonu ^{[42
,43
,44
]}

Johnson, Toby ^{[45
,46
,47
,48
]}

Ketkar, Shamika ^{[41
]}

Kraft, Peter ^{[49
,50
]}

Mangino, Massimo ^{[20
]}

Prokopenko, Inga ^{[15
,51
]}

Absher, Devin ^{[52
]}

Albrecht, Eva ^{[35
]}

Ernst, Florian ^{[53
]}

Glazer, Nicole L. ^{[54
,55
]}

Hayward, Caroline ^{[56
]}

机构：

[1] Univ Exeter, Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England

[2] Erasmus Sch Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands

[3] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands

[4] NCHA, NGI, NL-42300 RC Leiden, Netherlands

[5] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[6] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada

[7] Natl Canc Inst, Natl Inst Hlth, Divis Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA

[8] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[9] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA

[10] Childrens Hosp, Program Gen, Boston, MA 02115 USA

[11] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[12] MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[13] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[14] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

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

[16] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

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

[18] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[19] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[20] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[21] Queensland Inst Med Res, Queensland Stat Genet Lab, Queensland 4006, Australia

[22] deCODE Genet, IS-101 Reykjavik, Iceland

[23] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[24] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

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

[26] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA

[27] Iceland Heart Assoc, Kopavogur, Iceland

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

[29] McGill Univ, Montreal, PQ H3A 1A4, Canada

[30] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada

[31] McGill Univ, Ctr Hlth, Dept Human Genet, Montreal, PQ H3G 1A4, Canada

[32] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA

[33] Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA

[34] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany

[35] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany

[36] Addenbrookes Hosp, Inst Met Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England

[37] Univ Melbourne, Fac Land & Environm, Parkville, Vic 3010, Australia

[38] Dept Primary Ind, Bundoora, Vic 3086, Australia

[39] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden

[40] Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Fac Med, N-7489 Trondheim, Norway

[41] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[42] Univ Tartu, Estonian Genome Ctr, EE-50410 Tartu, Estonia

[43] Estonian Bioctr, EE-51010 Tartu, Estonia

[44] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia

[45] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland

[46] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[47] Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England

[48] Univ London, William Harvey Res Inst, Barts & London Genome Ctr, Barts & London Sch Med & Dent, London EC1M6BQ, England

[49] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[50] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

来源：

NATURE | 2010年 / 467卷 / 7317期

基金：

瑞典研究理事会; 瑞士国家科学基金会; 英国惠康基金; 澳大利亚研究理事会; 英国医学研究理事会; 芬兰科学院; 美国国家卫生研究院;

关键词：

WIDE ASSOCIATION; COMMON VARIANTS; HERITABILITY; ADULT;

D O I：

10.1038/nature09410

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：

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use 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(2,3). 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 among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

引用

页码：832 / 838

页数：7

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