Identification of ten loci associated with height highlights new biological pathways in human growth

被引：456

作者：

Lettre, Guillaume ^{[1
,2
,3
]}

Jackson, Anne U. ^{[4
]}

Gieger, Christian ^{[5
,6
]}

Schumacher, Fredrick R. ^{[7
,8
,9
]}

Berndt, Sonja I. ^{[10
]}

Sanna, Serena ^{[4
,11
]}

Eyheramendy, Susana ^{[5
,6
]}

Voight, Benjamin F. ^{[1
,12
]}

Butler, Johannah L. ^{[2
,3
]}

Guiducci, Candace ^{[1
]}

Illig, Thomas ^{[5
]}

Hackett, Rachel ^{[1
]}

Heid, Iris M. ^{[5
,6
]}

Jacobs, Kevin B. ^{[13
]}

Lyssenko, Valeriya ^{[14
]}

Uda, Manuela ^{[11
]}

Boehnke, Michael ^{[4
]}

Chanock, Stephen J. ^{[15
]}

Groop, Leif C. ^{[14
,16
,17
]}

Hu, Frank B. ^{[7
,8
,9
,18
]}

Isomaa, Bo ^{[19
,20
]}

Kraft, Peter ^{[9
]}

Peltonen, Leena ^{[1
,21
,22
,23
]}

Salomaa, Veikko ^{[24
]}

Schlessinger, David ^{[25
]}

Hunter, David J. ^{[1
,7
,8
,9
,18
]}

Hayes, Richard B. ^{[10
]}

Abecasis, Goncalo R. ^{[4
]}

Wichmann, H-Erich ^{[5
,6
]}

Mohlke, Karen L. ^{[26
]}

Hirschhorn, Joel N. ^{[1
,2
,3
,27
]}

机构：

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

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

[3] Childrens Hosp, Program Genom, Boston, MA 02115 USA

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

[5] GSF Natl Res Ctr Environm & Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany

[6] Univ Munich, Dept Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany

[7] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Boston, MA 02115 USA

[9] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA

[10] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA

[11] Cittadella Univ Monserrato, INN, Consiglio Nazl Ric, I-09042 Cagliari, Italy

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

[13] Bioinformed Consulting Serv, Gaithersburg, MD 20877 USA

[14] Lund Univ, Dept Clin Sci Diabetes & Endocrinol, Malmo Univ Hosp, S-20502 Malmo, Sweden

[15] NCI, NIH, DHHS, Lab Translat Genom,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[16] Univ Helsinki, Dept Med, Helsinki Univ Cent Hosp, Helsinki, Finland

[17] Univ Helsinki, Res Program Mol Med, Helsinki, Finland

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

[19] Malmska Municipal Hlth Ctr & Hosp, Pietarsaari, Finland

[20] Folkhalsan Res Ctr, Helsinki, Finland

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

[22] Univ Helsinki, Dept Mol Med, Natl Publ Hlth Inst, FI-00014 Helsinki, Finland

[23] Univ Helsinki, Dept Mol Med, Dept Med Genet, FI-00014 Helsinki, Finland

[24] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, FI-00300 Helsinki, Finland

[25] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA

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

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

来源：

NATURE GENETICS | 2008年 / 40卷 / 05期

基金：

美国国家卫生研究院; 芬兰科学院;

关键词：

D O I：

10.1038/ng.125

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet- undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in 410,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for similar to 2% of the population variation in height. Individuals with <= 8 height-increasing alleles and >= 16 height-increasing alleles differ in height by similar to 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.

引用

页码：584 / 591

页数：8

共 40 条

[1] A haplotype map of the human genome [J].

Altshuler, D ;

Brooks, LD ;

Chakravarti, A ;

Collins, FS ;

Daly, MJ ;

Donnelly, P ;

Gibbs, RA ;

Belmont, JW ;

Boudreau, A ;

Leal, SM ;

Hardenbol, P ;

Pasternak, S ;

Wheeler, DA ;

Willis, TD ;

Yu, FL ;

Yang, HM ;

Zeng, CQ ;

Gao, Y ;

Hu, HR ;

Hu, WT ;

Li, CH ;

Lin, W ;

Liu, SQ ;

Pan, H ;

Tang, XL ;

Wang, J ;

Wang, W ;

Yu, J ;

Zhang, B ;

Zhang, QR ;

Zhao, HB ;

Zhao, H ;

Zhou, J ;

Gabriel, SB ;

Barry, R ;

Blumenstiel, B ;

Camargo, A ;

Defelice, M ;

Faggart, M ;

Goyette, M ;

Gupta, S ;

Moore, J ;

Nguyen, H ;

Onofrio, RC ;

Parkin, M ;

Roy, J ;

Stahl, E ;

Winchester, E ;

Ziaugra, L ;

Shen, Y .

NATURE, 2005, 437 (7063) :1299-1320

[2] CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas [J].

Asp, Julia ;

Persson, Fredrik ;

Kost-Alimova, Maria ;

Stenman, Goeran .

GENES CHROMOSOMES & CANCER, 2006, 45 (09) :820-828

[3] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[4] Demonstrating stratification in a European American population [J].

Campbell, CD ;

Ogburn, EL ;

Lunetta, KL ;

Lyon, HN ;

Freedman, ML ;

Groop, LC ;

Altshuler, D ;

Ardlie, KG ;

Hirschhorn, JN .

NATURE GENETICS, 2005, 37 (08) :868-872

[5] Family-based association tests for genomewide association scans [J].

Chen, Wei-Min ;

Abecasis, Goncalo R. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (05) :913-926

[6] Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes [J].

Chikuda, H ;

Kugimiya, F ;

Hoshi, K ;

Ikeda, T ;

Ogasawara, T ;

Shimoaka, T ;

Kawano, H ;

Kamekura, S ;

Tsuchida, A ;

Yokoi, N ;

Nakamura, K ;

Komeda, K ;

Chung, UI ;

Kawaguchi, H .

GENES & DEVELOPMENT, 2004, 18 (19) :2418-2429

[7] Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein [J].

Chuang, PT ;

McMahon, AP .

NATURE, 1999, 397 (6720) :617-621

[8]

Fisher R. A., 1918, T ROY SOC EDINBURGH, V52, P399, DOI [10.1017/S0080456800012163, DOI 10.1017/S0080456800012163]

[9] A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity [J].

Frayling, Timothy M. ;

Timpson, Nicholas J. ;

Weedon, Michael N. ;

Zeggini, Eleftheria ;

Freathy, Rachel M. ;

Lindgren, Cecilia M. ;

Perry, John R. B. ;

Elliott, Katherine S. ;

Lango, Hana ;

Rayner, Nigel W. ;

Shields, Beverley ;

Harries, Lorna W. ;

Barrett, Jeffrey C. ;

Ellard, Sian ;

Groves, Christopher J. ;

Knight, Bridget ;

Patch, Ann-Marie ;

Ness, Andrew R. ;

Ebrahim, Shah ;

Lawlor, Debbie A. ;

Ring, Susan M. ;

Ben-Shlomo, Yoav ;

Jarvelin, Marjo-Riitta ;

Sovio, Ulla ;

Bennett, Amanda J. ;

Melzer, David ;

Ferrucci, Luigi ;

Loos, Ruth J. F. ;

Barroso, Ines ;

Wareham, Nicholas J. ;

Karpe, Fredrik ;

Owen, Katharine R. ;

Cardon, Lon R. ;

Walker, Mark ;

Hitman, Graham A. ;

Palmer, Colin N. A. ;

Doney, Alex S. F. ;

Morris, Andrew D. ;

Smith, George Davey ;

Hattersley, Andrew T. ;

McCarthy, Mark I. .

SCIENCE, 2007, 316 (5826) :889-894

[10] Height, leg length, and cancer risk: A systematic review [J].

Gunnell, D ;

Okasha, M ;

Smith, GD ;

Oliver, SE ;

Sandhu, J ;

Holly, JMP .

EPIDEMIOLOGIC REVIEWS, 2001, 23 (02) :313-342

← 1 2 3 4 →