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

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Kettunen, Johannes ;

Niinimaki, Jaakko ;

Karppinen, Jaro ;

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[42] Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction [J].

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Gupta, Ramneek ;

Grotmol, Tom ;

Haugen, Trine B. ;

Karlsson, Robert ;

Litchfield, Kevin ;

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Pyle, Louise C. ;

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Thorsson, Vesteinn ;

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Chambert, Kimberly ;

Moran, Jennifer L. ;

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Akterin, Susanne ;

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Craddock, Nick ;

de Leeuw, Christiaan ;

Durmishi, Naser ;

Gill, Michael ;

Golimbet, Vera ;

Hamshere, Marian L. ;

Holmans, Peter ;

Hougaard, David M. ;

Kendler, Kenneth S. ;

Lin, Kuang ;

Morris, Derek W. ;

Mors, Ole ;

Mortensen, Preben B. ;

Neale, Benjamin M. ;

O'Neill, Francis A. ;

Owen, Michael J. ;

Milovancevic, Milica Pejovic ;

Posthuma, Danielle ;

Powell, John ;

Richards, Alexander L. ;

Riley, Brien P. ;

Ruderfer, Douglas ;

Rujescu, Dan ;

Sigurdsson, Engilbert ;

Silagadze, Teimuraz ;

Smit, August B. ;

Stefansson, Hreinn ;

Steinberg, Stacy .

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[46] Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia [J].

Li, Zhiqiang ;

Chen, Jianhua ;

Yu, Hao ;

He, Lin ;

Xu, Yifeng ;

Zhang, Dai ;

Yi, Qizhong ;

Li, Changgui ;

Li, Xingwang ;

Shen, Jiawei ;

Song, Zhijian ;

Ji, Weidong ;

Wang, Meng ;

Zhou, Juan ;

Chen, Boyu ;

Liu, Yahui ;

Wang, Jiqiang ;

Wang, Peng ;

Yang, Ping ;

Wang, Qingzhong ;

Feng, Guoyin ;

Liu, Benxiu ;

Sun, Wensheng ;

Li, Baojie ;

He, Guang ;

Li, Weidong ;

Wan, Chunling ;

Xu, Qi ;

Li, Wenjin ;

Wen, Zujia ;

Liu, Ke ;

Huang, Fang ;

Ji, Jue ;

Ripke, Stephan ;

Yue, Weihua ;

Sullivan, Patrick F. ;

O'Donovan, Michael C. ;

Shi, Yongyong .

NATURE GENETICS, 2017, 49 (11) :1576-+

[47] Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture [J].

Estrada, Karol ;

Styrkarsdottir, Unnur ;

Evangelou, Evangelos ;

Hsu, Yi-Hsiang ;

Duncan, Emma L. ;

Ntzani, Evangelia E. ;

Oei, Ling ;

Albagha, Omar M. E. ;

Amin, Najaf ;

Kemp, John P. ;

Koller, Daniel L. ;

Li, Guo ;

Liu, Ching-Ti ;

Minster, Ryan L. ;

Moayyeri, Alireza ;

Vandenput, Liesbeth ;

Willner, Dana ;

Xiao, Su-Mei ;

Yerges-Armstrong, Laura M. ;

Zheng, Hou-Feng ;

Alonso, Nerea ;

Eriksson, Joel ;

Kammerer, Candace M. ;

Kaptoge, Stephen K. ;

Leo, Paul J. ;

Thorleifsson, Gudmar ;

Wilson, Scott G. ;

Wilson, James F. ;

Aalto, Ville ;

Alen, Markku ;

Aragaki, Aaron K. ;

Aspelund, Thor ;

Center, Jacqueline R. ;

Dailiana, Zoe ;

Duggan, David J. ;

Garcia, Melissa ;

Garcia-Giralt, Natalia ;

Giroux, Sylvie ;

Hallmans, Goran ;

Hocking, Lynne J. ;

Husted, Lise Bjerre ;

Jameson, Karen A. ;

Khusainova, Rita ;

Kim, Ghi Su ;

Kooperberg, Charles ;

Koromila, Theodora ;

Kruk, Marcin ;

Laaksonen, Marika ;

Lacroix, Andrea Z. ;

Lee, Seung Hun .

NATURE GENETICS, 2012, 44 (05) :491-+

[48] Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis [J].

Whiffin, Nicola ;

Hosking, Fay J. ;

Farrington, Susan M. ;

Palles, Claire ;

Dobbins, Sara E. ;

Zgaga, Lina ;

Lloyd, Amy ;

Kinnersley, Ben ;

Gorman, Maggie ;

Tenesa, Albert ;

Broderick, Peter ;

Wang, Yufei ;

Barclay, Ella ;

Hayward, Caroline ;

Martin, Lynn ;

Buchanan, Daniel D. ;

Win, Aung Ko ;

Hopper, John ;

Jenkins, Mark ;

Lindor, Noralane M. ;

Newcomb, Polly A. ;

Gallinger, Steve ;

Conti, David ;

Schumacher, Fred ;

Casey, Graham ;

Liu, Tao ;

Campbell, Harry ;

Lindblom, Annika ;

Houlston, Richard S. ;

Tomlinson, Ian P. ;

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