Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

被引：485

作者：

Berndt, Sonja I. ^{[1
]}

Gustafsson, Stefan ^{[2
,3
]}

Maegi, Reedik ^{[4
,5
]}

Ganna, Andrea ^{[3
]}

Wheeler, Eleanor ^{[6
]}

Feitosa, Mary F. ^{[7
]}

Justice, Anne E. ^{[8
]}

Monda, Keri L. ^{[8
,9
]}

Croteau-Chonka, Damien C. ^{[10
]}

Day, Felix R. ^{[11
]}

Esko, Tonu ^{[5
,12
]}

Fall, Tove ^{[3
]}

Ferreira, Teresa ^{[4
]}

Gentilini, Davide ^{[13
]}

Jackson, Anne U. ^{[14
]}

Luan, Jian'an ^{[11
]}

Randall, Joshua C. ^{[4
,6
]}

Vedantam, Sailaja ^{[15
,16
,17
,18
,19
]}

Willer, Cristen J. ^{[20
,21
,22
]}

Winkler, Thomas W. ^{[23
]}

Wood, Andrew R. ^{[24
]}

Workalemahu, Tsegaselassie ^{[25
,26
,27
]}

Hu, Yi-Juan

Lee, Sang Hong ^{[28
]}

Liang, Liming ^{[29
,30
]}

Lin, Dan-Yu ^{[31
]}

Min, Josine L. ^{[4
]}

Neale, Benjamin M. ^{[32
]}

Thorleifsson, Gudmar ^{[33
]}

Yang, Jian ^{[34
,35
]}

Albrecht, Eva ^{[36
]}

Amin, Najaf ^{[36
]}

Bragg-Gresham, Jennifer L. ^{[14
]}

Cadby, Gemma ^{[38
,39
,40
]}

den Heijer, Martin ^{[41
]}

Eklund, Niina ^{[42
]}

Fischer, Krista ^{[5
]}

Goel, Anuj ^{[43
]}

Hottenga, Jouke-Jan ^{[44
]}

Huffman, Jennifer E. ^{[45
]}

Jarick, Ivonne ^{[46
]}

Johansson, Asa ^{[47
,48
]}

Johnson, Toby ^{[49
,50
]}

Kanoni, Stavroula ^{[6
]}

Kleber, Marcus E. ^{[51
]}

Koenig, Inke R. ^{[52
,53
]}

Kristiansson, Kati ^{[42
]}

Kutalik, Zoltn ^{[54
,55
]}

Lamina, Claudia ^{[56
]}

Lecoeur, Cecile ^{[57
,58
]}

机构：

[1] NCI, US Dept HHS, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA

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

[3] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

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

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

[6] Wellcome Trust Sanger Inst, Cambridge, England

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

[8] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA

[9] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA USA

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

[11] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England

[12] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[13] Ist Auxol Italiano, Dept Mol Biol, Milan, Italy

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

[15] Childrens Hosp, Div Genet, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA

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

[17] Broad Inst, Metab Initiat, Cambridge, MA USA

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

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

[20] Univ Michigan, Dept Internal Med Cardiovasc, Ann Arbor, MI 48109 USA

[21] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[22] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[23] Univ Regensburg, Med Ctr, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany

[24] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

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

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

[27] Harvard Univ, Sch Med, Boston, MA USA

[28] Emory Univ, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA

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

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

[31] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[32] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[33] deCODE Genet, Reykjavik, Iceland

[34] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

[35] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

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

[37] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[38] Ontario Inst Canc Res, Toronto, ON, Canada

[39] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada

[40] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Crawley, WA, Australia

[41] Vrije Univ Amsterdam, Med Ctr, Dept Internal Med, Amsterdam, Netherlands

[42] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Unit Publ Hlth Gen, Helsinki, Finland

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

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

[45] Western Gen Hosp, MRC, Inst Genet & Mol Med, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[46] Univ Marburg, Inst Med Biometry & Epidemiol, Marburg, Germany

[47] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden

[48] Univ Uppsala Hosp, Uppsala Clin Res Ctr, Uppsala, Sweden

[49] Queen Mary Univ London, Barts & London Sch Med & Dent, Genome Ctr, London, England

[50] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

来源：

NATURE GENETICS | 2013年 / 45卷 / 05期

基金：

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

关键词：

BODY-MASS INDEX; MISSING HERITABILITY; COMMON VARIANTS; EXTREME OBESITY; CONFER RISK; EARLY-ONSET; ASSOCIATION; POPULATION; EXPRESSION; SORTILIN;

D O I：

10.1038/ng.2606

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

引用

页码：501 / U69

页数：14

共 54 条

[1] Hundreds of variants clustered in genomic loci and biological pathways affect human height
Allen, Hana Lango
Estrada, Karol
Lettre, Guillaume
Berndt, Sonja I.
Weedon, Michael N.
Rivadeneira, Fernando
Willer, Cristen J.
Jackson, Anne U.
Vedantam, Sailaja
Raychaudhuri, Soumya
Ferreira, Teresa
Wood, Andrew R.
Weyant, Robert J.
Segre, Ayellet V.
Speliotes, Elizabeth K.
Wheeler, Eleanor
Soranzo, Nicole
Park, Ju-Hyun
Yang, Jian
Gudbjartsson, Daniel
Heard-Costa, Nancy L.
Randall, Joshua C.
Qi, Lu
Smith, Albert Vernon
Maegi, Reedik
Pastinen, Tomi
Liang, Liming
Heid, Iris M.
Luan, Jian'an
Thorleifsson, Gudmar
Winkler, Thomas W.
Goddard, Michael E.
Lo, Ken Sin
Palmer, Cameron
Workalemahu, Tsegaselassie
Aulchenko, Yurii S.
Johansson, Asa
Zillikens, M. Carola
Feitosa, Mary F.
Esko, Tonu
Johnson, Toby
Ketkar, Shamika
Kraft, Peter
Mangino, Massimo
Prokopenko, Inga
Absher, Devin
Albrecht, Eva
Ernst, Florian
Glazer, Nicole L.
Hayward, Caroline
[J]. NATURE, 2010, 467 (7317) : 832 - 838
[2] Common nonsynonymous variants in PCSK1 confer risk of obesity
Benzinou, Michael
Creemers, John W. M.
Choquet, Helene
Lobbens, Stephane
Dina, Christian
Durand, Emmanuelle
Guerardel, Audrey
Boutin, Philippe
Jouret, Beatrice
Heude, Barbara
Balkau, Beverley
Tichet, Jean
Marre, Michel
Potoczna, Natascha
Horber, Fritz
Le Stunff, Catherine
Czernichow, Sebastien
Sandbaek, Annelli
Lauritzen, Torsten
Borch-Johnsen, Knut
Andersen, Gitte
Kiess, Wieland
Koerner, Antje
Kovacs, Peter
Jacobson, Peter
Carlsson, Lena M. S.
Walley, Andrew J.
Jorgensen, Torben
Hansen, Torben
Pedersen, Oluf
Meyre, David
Froguel, Philippe
[J]. NATURE GENETICS, 2008, 40 (08) : 943 - 945
[3] A genome-wide association meta-analysis identifies new childhood obesity loci
Bradfield, Jonathan P.
Taal, H. Rob
Timpson, Nicholas J.
Scherag, Andre
Lecoeur, Cecile
Warrington, Nicole M.
Hypponen, Elina
Holst, Claus
Valcarcel, Beatriz
Thiering, Elisabeth
Salem, Rany M.
Schumacher, Fredrick R.
Cousminer, Diana L.
Sleiman, Patrick M. A.
Zhao, Jianhua
Berkowitz, Robert I.
Vimaleswaran, Karani S.
Jarick, Ivonne
Pennell, Craig E.
Evans, David M.
St Pourcain, Beate
Berry, Diane J.
Mook-Kanamori, Dennis O.
Hofman, Albert
Rivadeneira, Fernando
Uitterlinden, Andre G.
van Duijn, Cornelia M.
van der Valk, Ralf J. P.
de Jongste, Johan C.
Postma, Dirkje S.
Boomsma, Dorret I.
Gauderman, W. James
Hassanein, Mohamed T.
Lindgren, Cecilia M.
Magi, Reedik
Boreham, Colin A. G.
Neville, Charlotte E.
Moreno, Luis A.
Elliott, Paul
Pouta, Anneli
Hartikainen, Anna-Liisa
Li, Mingyao
Raitakari, Olli
Lehtimaki, Terho
Eriksson, Johan G.
Palotie, Aarno
Dallongeville, Jean
Das, Shikta
Deloukas, Panos
McMahon, George
[J]. NATURE GENETICS, 2012, 44 (05) : 526 - +
[4] Common Variants Show Predicted Polygenic Effects on Height in the Tails of the Distribution, Except in Extremely Short Individuals
Chan, Yingleong
Holmen, Oddgeir L.
Dauber, Andrew
Vatten, Lars
Havulinna, Aki S.
Skorpen, Frank
Kvaloy, Kirsti
Silander, Kaisa
Nguyen, Thutrang T.
Willer, Cristen
Boehnke, Michael
Perola, Markus
Palotie, Aarno
Salomaa, Veikko
Hveem, Kristian
Frayling, Timothy M.
Hirschhorn, Joel N.
Weedon, Michael N.
[J]. PLOS GENETICS, 2011, 7 (12):
[5] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians
Cho, Yoon Shin
Chen, Chien-Hsiun
Hu, Cheng
Long, Jirong
Ong, Rick Twee Hee
Sim, Xueling
Takeuchi, Fumihiko
Wu, Ying
Go, Min Jin
Yamauchi, Toshimasa
Chang, Yi-Cheng
Kwak, Soo Heon
Ma, Ronald C. W.
Yamamoto, Ken
Adair, Linda S.
Aung, Tin
Cai, Qiuyin
Chang, Li-Ching
Chen, Yuan-Tsong
Gao, Yutang
Hu, Frank B.
Kim, Hyung-Lae
Kim, Sangsoo
Kim, Young Jin
Lee, Jeannette Jen-Mai
Lee, Nanette R.
Li, Yun
Liu, Jian Jun
Lu, Wei
Nakamura, Jiro
Nakashima, Eitaro
Ng, Daniel Peng-Keat
Tay, Wan Ting
Tsai, Fuu-Jen
Wong, Tien Yin
Yokota, Mitsuhiro
Zheng, Wei
Zhang, Rong
Wang, Congrong
So, Wing Yee
Ohnaka, Keizo
Ikegami, Hiroshi
Hara, Kazuo
Cho, Young Min
Cho, Nam H.
Chang, Tien-Jyun
Bao, Yuqian
Hedman, Asa K.
Morris, Andrew P.
McCarthy, Mark I.
[J]. NATURE GENETICS, 2012, 44 (01) : 67 - U97
[6] Multiple rare Alleles contribute to low plasma levels of HDL cholesterol
Cohen, JC
Kiss, RS
Pertsemlidis, A
Marcel, YL
McPherson, R
Hobbs, HH
[J]. SCIENCE, 2004, 305 (5685) : 869 - 872
[7] Common body mass index-associated variants confer risk of extreme obesity
Cotsapas, Chris
Speliotes, Elizabeth K.
Hatoum, Ida J.
Greenawalt, Danielle M.
Dobrin, Radu
Lum, Pek Y.
Suver, Christine
Chudin, Eugene
Kemp, Daniel
Reitman, Marc
Voight, Benjamin F.
Neale, Benjamin M.
Schadt, Eric E.
Hirschhorn, Joel N.
Kaplan, Lee M.
Daly, Mark J.
[J]. HUMAN MOLECULAR GENETICS, 2009, 18 (18) : 3502 - 3507
[8] Proteomic Analysis of Native Hepatocyte Nuclear Factor-4α (HNF4α) Isoforms, Phosphorylation Status, and Interactive Cofactors
Daigo, Kenji
Kawamura, Takeshi
Ohta, Yoshihiro
Ohashi, Riuko
Katayose, Satoshi
Tanaka, Toshiya
Aburatani, Hiroyuki
Naito, Makoto
Kodama, Tatsuhiko
Ihara, Sigeo
Hamakubo, Takao
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (01) : 674 - 686
[9] Evaluation of common genetic variants identified by GWAS for early onset and morbid obesity in population-based samples
den Hoed, M.
Luan, J.
Langenberg, C.
Cooper, C.
Sayer, A. A.
Jameson, K.
Kumari, M.
Kivimaki, M.
Hingorani, A. D.
Grontved, A.
Khaw, K-T
Ekelund, U.
Wareham, N. J.
Loos, R. J. F.
[J]. INTERNATIONAL JOURNAL OF OBESITY, 2013, 37 (02) : 191 - 196
[10] A genome-wide association study of global gene expression
Dixon, Anna L.
Liang, Liming
Moffatt, Miriam F.
Chen, Wei
Heath, Simon
Wong, Kenny C. C.
Taylor, Jenny
Burnett, Edward
Gut, Ivo
Farrall, Martin
Lathrop, G. Mark
Abecasis, Goncalo R.
Cookson, William O. C.
[J]. NATURE GENETICS, 2007, 39 (10) : 1202 - 1207

← 1 2 3 4 5 6 →