Defining the role of common variation in the genomic and biological architecture of adult human height.

Defining the role of common variation in the genomic and biological architecture of adult human height.
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DOI:
10.1038/ng.3097
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发表时间:
2014-11
期刊:
影响因子:
30.8
通讯作者:
Frayling, Timothy M.
Frayling, Timothy M.
中科院分区:
生物学1区
文献类型:
--
作者:
Wood, Andrew R.;Esko, Tonu;Yang, Jian;Vedantam, Sailaja;Pers, Tune H.;Gustafsson, Stefan;Chun, Audrey Y.;Estrada, Karol;Luan, Jian'an;Kutalik, Zoltan;Amin, Najaf;Buchkovich, Martin L.;Croteau-Chonka, Damien C.;Day, Felix R.;Duan, Yanan;Fall, Tove;Fehrmann, Rudolf;Ferreira, Teresa;Jackson, Anne U.;Karjalainen, Juha;Lo, Ken Sin;Locke, Adam E.;Maegi, Reedik;Mihailov, Evelin;Porcu, Eleonora;Randall, Joshua C.;Scherag, Andre;Vinkhuyzen, Anna A. E.;Westra, Harm-Jan;Winkler, Thomas W.;Workalemahu, Tsegaselassie;Zhao, Jing Hua;Absher, Devin;Albrecht, Eva;Anderson, Denise;Baron, Jeffrey;Beekman, Marian;Demirkan, Ayse;Ehret, Georg B.;Feenstra, Bjarke;Feitosa, Mary F.;Fischer, Krista;Fraser, Ross M.;Goel, Anuj;Gong, Jian;Justice, Anne E.;Kanoni, Stavroula;Kleber, Marcus E.;Kristiansson, Kati;Lim, Unhee;Lotay, Vaneet;Lui, Julian C.;Mangino, Massimo;Leach, Irene Mateo;Medina-Gomez, Carolina;Nalls, Michael A.;Nyholt, Dale R.;Palmer, Cameron D.;Pasko, Dorota;Pechlivanis, Sonali;Prokopenko, Inga;Ried, Janina S.;Ripke, Stephan;Shungin, Dmitry;Stancakova, Alena;Strawbridge, Rona J.;Sung, Yun Ju;Tanaka, Toshiko;Teumer, Alexander;Trompet, Stella;van der Laan, Sander W.;van Setten, Jessica;Van Vliet-Ostaptchouk, Jana V.;Wang, Zhaoming;Yengo, Loic;Zhang, Weihua;Afzal, Uzma;Arnloev, Johan;Arscott, Gillian M.;Bandinelli, Stefania;Barrett, Amy;Bellis, Claire;Bennett, Amanda J.;Berne, Christian;Blueher, Matthias;Bolton, Jennifer L.;Boettcher, Yvonne;Boyd, Heather A.;Bruinenberg, Marcel;Buckley, Brendan M.;Buyske, Steven;Caspersen, Ida H.;Chines, Peter S.;Clarke, Robert;Claudi-Boehm, Simone;Cooper, Matthew;Daw, E. Warwick;De Jong, Pim A.;Deelen, Joris;Delgado, Graciela;Denny, Josh C.;Dhonukshe-Rutten, Rosalie;Dimitriou, Maria;Doney, Alex S. F.;Doerr, Marcus;Eklund, Niina;Eury, Elodie;Folkersen, Lasse;Garcia, Melissa E.;Geller, Frank;Giedraitis, Vilmantas;Go, Alan S.;Grallert, Harald;Grammer, Tanja B.;Graessler, Juergen;Groenberg, Henrik;de Groot, Lisette C. P. G. M.;Groves, Christopher J.;Haessler, Jeffrey;Hall, Per;Haller, Toomas;Hallmans, Goran;Hannemann, Anke;Hartman, Catharina A.;Hassinen, Maija;Hayward, Caroline;Heard-Costa, Nancy L.;Helmer, Quinta;Hemani, Gibran;Henders, Anjali K.;Hillege, Hans L.;Hlatky, Mark A.;Hoffmann, Wolfgang;Hoffmann, Per;Holmen, Oddgeir;Houwing-Duistermaat, Jeanine J.;Illig, Thomas;Isaacs, Aaron;James, Alan L.;Jeff, Janina;Johansen, Bent;Johansson, Asa;Jolley, Jennifer;Juliusdottir, Thorhildur;Junttila, Juhani;Kho, Abel N.;Kinnunen, Leena;Klopp, Norman;Kocher, Thomas;Kratzer, Wolfgang;Lichtner, Peter;Lind, Lars;Lindstroem, Jaana;Lobbens, Stephane;Lorentzon, Mattias;Lu, Yingchang;Lyssenko, Valeriya;Magnusson, Patrik K. E.;Mahajan, Anubha;Maillard, Marc;McArdle, Wendy L.;McKenzie, Colin A.;McLachlan, Stela;McLaren, Paul J.;Menni, Cristina;Merger, Sigrun;Milani, Lili;Moayyeri, Alireza;Monda, Keri L.;Morken, Mario A.;Mueller, Gabriele;Mueller-Nurasyid, Martina;Musk, Arthur W.;Narisu, Narisu;Nauck, Matthias;Nolte, Ilja M.;Noethen, Markus M.;Oozageer, Laticia;Pilz, Stefan;Rayner, Nigel W.;Renstrom, Frida;Robertson, Neil R.;Rose, Lynda M.;Roussel, Ronan;Sanna, Serena;Scharnagl, Hubert;Scholtens, Salome;Schumacher, Fredrick R.;Schunkert, Heribert;Scott, Robert A.;Sehmi, Joban;Seufferlein, Thomas;Shin, Jianxin;Silventoinen, Karri;Smit, Johannes H.;Smith, Albert Vernon;Smolonska, Joanna;Stanton, Alice V.;Stirrups, Kathleen;Stott, David J.;Stringham, Heather M.;Sundstrom, Johan;Swertz, Morris A.;Syvanen, Ann-Christine;Tayo, Bamidele O.;Thorleifsson, Gudmar;Tyrer, Jonathan P.;van Dijk, Suzanne;van Schoor, Natasja M.;van der Velde, Nathalie;van Heemst, Diana;van Oort, Floor V. A.;Vermeulen, Sita H.;Verweij, Niek;Vonk, Judith M.;Waite, Lindsay L.;Waldenberger, Melanie;Wennauer, Roman;Wilkens, Lynne R.;Willenborg, Christina;Wilsgaard, Tom;Wojczynski, Mary K.;Wong, Andrew;Wright, Alan F.;Zhang, Qunyuan;Arveiler, Dominique;Bakker, Stephan J. L.;Beilby, John;Bergman, Richard N.;Bergmann, Sven;Biffar, Reiner;Blangero, John;Boomsma, Dorret I.;Bornstein, Stefan R.;Bovet, Pascal;Brambilla, Paolo;Brown, Morris J.;Campbell, Harry;Caulfield, Mark J.;Chakravarti, Aravinda;Collins, Rory;Collins, Francis S.;Crawford, Dana C.;Cupples, L. Adrienne;Danesh, John;de Faire, Ulf;den Ruijter, Hester M.;Erbel, Raimund;Erdmann, Jeanette;Eriksson, Johan G.;Farrall, Martin;Ferrannini, Ele;Ferrieres, Jean;Ford, Ian;Forouhi, Nita G.;Forrester, Terrence;Gansevoort, Ron T.;Gejman, Pablo V.;Gieger, Christian;Golay, Alain;Gottesman, Omri;Gudnason, Vilmundur;Gyllensten, Ulf;Haas, David W.;Hall, Alistair S.;Harris, Tamara B.;Hattersley, Andrew T.;Heath, Andrew C.;Hengstenberg, Christian;Hicks, Andrew A.;Hindorff, Lucia A.;Hingorani, Aroon D.;Hofman, Albert;Hovingh, G. Kees;Humphries, Steve E.;Hunt, Steven C.;Hypponen, Elina;Jacobs, Kevin B.;Jarvelin, Marjo-Riitta;Jousilahti, Pekka;Jula, Antti M.;Kaprio, Jaakko;Kastelein, John J. P.;Kayser, Manfred;Kee, Frank;Keinanen-Kiukaanniemi, Sirkka M.;Kiemeney, Lambertus A.;Kooner, Jaspal S.;Kooperberg, Charles;Koskinen, Seppo;Kovacs, Peter;Kraja, Aldi T.;Kumari, Meena;Kuusisto, Johanna;Lakka, Timo A.;Langenberg, Claudia;Le Marchand, Loic;Lehtimaki, Terho;Lupoli, Sara;Madden, Pamela A. F.;Mannisto, Satu;Manunta, Paolo;Marette, Andre;Matise, Tara C.;McKnight, Barbara;Meitinger, Thomas;Moll, Frans L.;Montgomery, Grant W.;Morris, Andrew D.;Morris, Andrew P.;Murray, Jeffrey C.;Nelis, Mari;Ohlsson, Claes;Oldehinkel, Albertine J.;Ong, Ken K.;Ouwehand, Willem H.;Pasterkamp, Gerard;Peters, Annette;Pramstaller, Peter P.;Price, Jackie F.;Qi, Lu;Raitakari, Olli T.;Rankinen, Tuomo;Rao, D. C.;Rice, Treva K.;Ritchie, Marylyn;Rudan, Igor;Salomaa, Veikko;Samani, Nilesh J.;Saramies, Jouko;Sarzynski, Mark A.;Schwarz, Peter E. H.;Sebert, Sylvain;Sever, Peter;Shuldiner, Alan R.;Sinisalo, Juha;Steinthorsdottir, Valgerdur;Stolk, Ronald P.;Tardif, Jean-Claude;Toenjes, Anke;Tremblay, Angelo;Tremoli, Elena;Virtamo, Jarmo;Vohl, Marie-Claude;Amouyel, Philippe;Asselbergs, Folkert W.;Assimes, Themistocles L.;Bochud, Murielle;Boehm, Bernhard O.;Boerwinkle, Eric;Bottinger, Erwin P.;Bouchard, Claude;Cauchi, Stephane;Chambers, John C.;Chanock, Stephen J.;Cooper, Richard S.;de Bakker, Paul I. W.;Dedoussis, George;Ferrucci, Luigi;Franks, Paul W.;Froguel, Philippe;Groop, Leif C.;Haiman, Christopher A.;Hamsten, Anders;Hayes, M. Geoffrey;Hui, Jennie;Hunter, David J.;Hveem, Kristian;Jukema, J. Wouter;Kaplan, Robert C.;Kivimaki, Mika;Kuh, Diana;Laakso, Markku;Liu, Yongmei;Martin, Nicholas G.;Maerz, Winfried;Melbye, Mads;Moebus, Susanne;Munroe, Patricia B.;Njolstad, Inger;Oostra, Ben A.;Palmer, Colin N. A.;Pedersen, Nancy L.;Perola, Markus;Perusse, Louis;Peters, Ulrike;Powell, Joseph E.;Power, Chris;Quertermous, Thomas;Rauramaa, Rainer;Reinmaa, Eva;Ridker, Paul M.;Rivadeneira, Fernando;Rotter, Jerome I.;Saaristo, Timo E.;Saleheen, Danish;Schlessinger, David;Slagboom, P. Eline;Snieder, Harold;Spector, Tim D.;Strauch, Konstantin;Stumvoll, Michael;Tuomilehto, Jaakko;Uusitupa, Matti;van der Harst, Pim;Voelzke, Henry;Walker, Mark;Wareham, Nicholas J.;Watkins, Hugh;Wichmann, H-Erich;Wilson, James F.;Zanen, Pieter;Deloukas, Panos;Heid, Iris M.;Lindgren, Cecilia M.;Mohlke, Karen L.;Speliotes, Elizabeth K.;Thorsteinsdottir, Unnur;Barroso, Ines;Fox, Caroline S.;North, Kari E.;Strachan, David P.;Beckmann, Jacques S.;Berndt, Sonja I.;Boehnke, Michael;Borecki, Ingrid B.;McCarthy, Mark I.;Metspalu, Andres;Stefansson, Kari;Uitterlinden, Andre G.;van Duijn, Cornelia M.;Franke, Lude;Willer, Cristen J.;Price, Alkes L.;Lettre, Guillaume;Loos, Ruth J. F.;Weedon, Michael N.;Ingelsson, Erik;O'Connell, Jeffrey R.;Abecasis, Goncalo R.;Chasman, Daniel I.;Goddard, Michael E.;Visscher, Peter M.;Hirschhorn, Joel N.;Frayling, Timothy M.

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使用来自253,288个个体的全基因组数据,我们确定了697个具有全基因组意义的变异,这些变异加在一起解释了成人身高五分之一的遗传力。通过在独立研究中测试不同数量的变异,我们发现最强关联的~2,000,~3,700和~9,500个SNP分别解释了~21%,~24%和~29%的表型变异。此外,所有常见的变异一起捕获了大多数(60%)的遗传性。这697个变异体聚集在423个座位上,富含已知参与生长的基因、途径和组织类型,并共同涉及早期研究中没有突出显示的基因和途径,例如通过成纤维细胞生长因子、WNT/β-连环蛋白和硫酸软骨素相关基因进行信号传递。我们发现了几个以前与人类骨骼生长无关的基因和途径,包括mTOR、骨钙素和透明质酸的结合。我们的结果表明,人类身高的遗传结构以非常大但有限数量(数千)的因果变异为特征。
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
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