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

Lango Allen, H., Estrada, K., Lettre, G., Berndt, S. I., Weedon, M. N., Rivadeneira, F., Willer, C. J., Jackson, A. U., Vedantam, S., Raychaudhuri, S., Ferreira, T., Wood, A. R., Weyant, R. J., Segre, A. V., Speliotes, E. K., Wheeler, E., Soranzo, N., Park, J. H., Yang, J., Gudbjartsson, D., Heard-Costa, N. L., Randall, J. C., Qi, L., Vernon Smith, A., Magi, R., Pastinen, T., Liang, L., Heid, I. M., Luan, J., Thorleifsson, G., Winkler, T. W., Goddard, M. E., Sin Lo, K., Palmer, C., Workalemahu, T., Aulchenko, Y. S., Johansson, A., Zillikens, M. C., Feitosa, M. F., Esko, T., Johnson, T., Ketkar, S., Kraft, P., Mangino, M., Prokopenko, I., Absher, D., Albrecht, E., Ernst, F., Glazer, N. L., Hayward, C., Hottenga, J. J., Jacobs, K. B., Knowles, J. W., Kutalik, Z., Monda, K. L., Polasek, O., Preuss, M., Rayner, N. W., Robertson, N. R., Steinthorsdottir, V., Tyrer, J. P., Voight, B. F., Wiklund, F., Xu, J., Zhao, J. H., Nyholt, D.R., Pellikka, N., Perola, M., Perry, J. R., Surakka, I., Tammesoo, M. L., Altmaier, E. L., Amin, N., Aspelund, T., Bhangale, T., Boucher, G., Chasman, D. I., Chen, C., Coin, L., Cooper, M. N., Dixon, A. L., Gibson, Q., Grundberg, E., Hao, K., Juhani Junttila, M., Kaplan, L. M., Kettunen, J., Konig, I. R., Kwan, T., Lawrence, R. W., Levinson, D. F., Lorentzon, M., McKnight, B., Morris, A. P., Muller, M., Suh Ngwa, J., Purcell, S., Rafelt, S., Salem, R. M., Salvi, E., Sanna, S., Shi, J., Sovio, U., Thompson, J. R., Turchin, M. C., Vandenput, L., Verlaan, D. J., Vitart, V., White, C. C., Ziegler, A., Almgren, P., Balmforth, A. J., Campbell, H., Citterio, L., De Grandi, A., Dominiczak, A., Duan, J., Elliott, P., Elosua, R., Eriksson, J. G., Freimer, N. B., Geus, E. J., Glorioso, N., Haiqing, S., Hartikainen, A. L., Havulinna, A. S., Hicks, A. A., Hui, J., Igl, W., Illig, T., Jula, A., Kajantie, E., Kilpelainen, T. O., Koiranen, M., Kolcic, I., Koskinen, S., Kovacs, P., Laitinen, J., Liu, J., Lokki, M. L., Marusic, A., Maschio, A., Meitinger, T., Mulas, A., Pare, G., Parker, A. N., Peden, J. F., Petersmann, A., Pichler, I., Pietilainen, K. H., Pouta, A., Ridderstrale, M., Rotter, J. I., Sambrook, J. G., Sanders, A. R., Schmidt, C. O., Sinisalo, J., Smit, J. H., Stringham, H. M., Bragi Walters, G., Widen, E., Wild, S. H., Willemsen, G., Zagato, L., Zgaga, L., Zitting, P., Alavere, H., Farrall, M., McArdle, W. L., Nelis, M., Peters, M. J., Ripatti, S., van Meurs, J. B., Aben, K. K., Ardlie, K. G., Beckmann, J. S., Beilby, J. P., Bergman, R. N., Bergmann, S., Collins, F. S., Cusi, D., den Heijer, M., Eiriksdottir, G., Gejman, P. V., Hall, A. S., Hamsten, A., Huikuri, H. V., Iribarren, C., Kahonen, M., Kaprio, J., Kathiresan, S., Kiemeney, L., Kocher, T., Launer, L. J., Lehtimaki, T., Melander, O., Mosley, T. H., Musk, A. W., Nieminen, M. S., O'Donnell, C. J., Ohlsson, C., Oostra, B., Palmer, L. J., Raitakari, O., Ridker, P. M., Rioux, J. D., Rissanen, A., Rivolta, C., Schunkert, H., Shuldiner, A. R., Siscovick, D. S., Stumvoll, M., Tonjes, A., Tuomilehto, J., van Ommen, G. J., Viikari, J., Heath, A. C., Martin, N. G., Montgomery, G. W., Province, M. A., Kayser, M., Arnold, A. M., Atwood, L. D., Boerwinkle, E., Chanock, S. J., Deloukas, P., Gieger, C., Gronberg, H., Hall, P., Hattersley, A. T., Hengstenberg, C., Hoffman, W., Lathrop, G. M., Salomaa, V., Schreiber, S., Uda, M., Waterworth, D., Wright, A. F., Assimes, T. L., Barroso, I., Hofman, A., Mohlke, K. L., Boomsma, D. I., Caulfield, M. J., Cupples, L. A., Erdmann, J., Fox, C. S., Gudnason, V., Gyllensten, U., Harris, T. B., Hayes, R. B., Jarvelin, M. R., Mooser, V., Munroe, P. B., Ouwehand, W. H., Penninx, B. W., Pramstaller, P. P., Quertermous, T., Rudan, I., Samani, N. J., Spector, T. D., Volzke, H., Watkins, H., Wilson, J. F., Groop, L. C., Haritunians, T., Hu, F. B., Kaplan, R. C., Metspalu, A., North, K. E., Schlessinger, D., Wareham, N. J., Hunter, D. J., O'Connell, J. R., Strachan, D. P., Wichmann, H. E., Borecki, I. B., van Duijn, C. M., Schadt, E. E., Thorsteinsdottir, U., Peltonen, L., Uitterlinden, A. G., Visscher, P. M., Chatterjee, N., Loos, R. J., Boehnke, M., McCarthy, M. I., Ingelsson, E., Lindgren, C. M., Abecasis, G. R., Stefansson, K., Frayling, T. M., & Hirschhorn, J. N. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature, 467(7317), pp. 832-838.

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Abstract

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, 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. 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.

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ID Code: 91982
Item Type: Journal Article
Refereed: Yes
Additional Information: Lango Allen, Hana
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
Vernon Smith, Albert
Magi, Reedik
Pastinen, Tomi
Liang, Liming
Heid, Iris M
Luan, Jian'an
Thorleifsson, Gudmar
Winkler, Thomas W
Goddard, Michael E
Sin Lo, Ken
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
Hottenga, Jouke-Jan
Jacobs, Kevin B
Knowles, Joshua W
Kutalik, Zoltan
Monda, Keri L
Polasek, Ozren
Preuss, Michael
Rayner, Nigel W
Robertson, Neil R
Steinthorsdottir, Valgerdur
Tyrer, Jonathan P
Voight, Benjamin F
Wiklund, Fredrik
Xu, Jianfeng
Zhao, Jing Hua
Nyholt, Dale R
Pellikka, Niina
Perola, Markus
Perry, John R B
Surakka, Ida
Tammesoo, Mari-Liis
Altmaier, Elizabeth L
Amin, Najaf
Aspelund, Thor
Bhangale, Tushar
Boucher, Gabrielle
Chasman, Daniel I
Chen, Constance
Coin, Lachlan
Cooper, Matthew N
Dixon, Anna L
Gibson, Quince
Grundberg, Elin
Hao, Ke
Juhani Junttila, M
Kaplan, Lee M
Kettunen, Johannes
Konig, Inke R
Kwan, Tony
Lawrence, Robert W
Levinson, Douglas F
Lorentzon, Mattias
McKnight, Barbara
Morris, Andrew P
Muller, Martina
Suh Ngwa, Julius
Purcell, Shaun
Rafelt, Suzanne
Salem, Rany M
Salvi, Erika
Sanna, Serena
Shi, Jianxin
Sovio, Ulla
Thompson, John R
Turchin, Michael C
Vandenput, Liesbeth
Verlaan, Dominique J
Vitart, Veronique
White, Charles C
Ziegler, Andreas
Almgren, Peter
Balmforth, Anthony J
Campbell, Harry
Citterio, Lorena
De Grandi, Alessandro
Dominiczak, Anna
Duan, Jubao
Elliott, Paul
Elosua, Roberto
Eriksson, Johan G
Freimer, Nelson B
Geus, Eco J C
Glorioso, Nicola
Haiqing, Shen
Hartikainen, Anna-Liisa
Havulinna, Aki S
Hicks, Andrew A
Hui, Jennie
Igl, Wilmar
Illig, Thomas
Jula, Antti
Kajantie, Eero
Kilpelainen, Tuomas O
Koiranen, Markku
Kolcic, Ivana
Koskinen, Seppo
Kovacs, Peter
Laitinen, Jaana
Liu, Jianjun
Lokki, Marja-Liisa
Marusic, Ana
Maschio, Andrea
Meitinger, Thomas
Mulas, Antonella
Pare, Guillaume
Parker, Alex N
Peden, John F
Petersmann, Astrid
Pichler, Irene
Pietilainen, Kirsi H
Pouta, Anneli
Ridderstrale, Martin
Rotter, Jerome I
Sambrook, Jennifer G
Sanders, Alan R
Schmidt, Carsten Oliver
Sinisalo, Juha
Smit, Jan H
Stringham, Heather M
Bragi Walters, G
Widen, Elisabeth
Wild, Sarah H
Willemsen, Gonneke
Zagato, Laura
Zgaga, Lina
Zitting, Paavo
Alavere, Helene
Farrall, Martin
McArdle, Wendy L
Nelis, Mari
Peters, Marjolein J
Ripatti, Samuli
van Meurs, Joyce B J
Aben, Katja K
Ardlie, Kristin G
Beckmann, Jacques S
Beilby, John P
Bergman, Richard N
Bergmann, Sven
Collins, Francis S
Cusi, Daniele
den Heijer, Martin
Eiriksdottir, Gudny
Gejman, Pablo V
Hall, Alistair S
Hamsten, Anders
Huikuri, Heikki V
Iribarren, Carlos
Kahonen, Mika
Kaprio, Jaakko
Kathiresan, Sekar
Kiemeney, Lambertus
Kocher, Thomas
Launer, Lenore J
Lehtimaki, Terho
Melander, Olle
Mosley, Tom H Jr
Musk, Arthur W
Nieminen, Markku S
O'Donnell, Christopher J
Ohlsson, Claes
Oostra, Ben
Palmer, Lyle J
Raitakari, Olli
Ridker, Paul M
Rioux, John D
Rissanen, Aila
Rivolta, Carlo
Schunkert, Heribert
Shuldiner, Alan R
Siscovick, David S
Stumvoll, Michael
Tonjes, Anke
Tuomilehto, Jaakko
van Ommen, Gert-Jan
Viikari, Jorma
Heath, Andrew C
Martin, Nicholas G
Montgomery, Grant W
Province, Michael A
Kayser, Manfred
Arnold, Alice M
Atwood, Larry D
Boerwinkle, Eric
Chanock, Stephen J
Deloukas, Panos
Gieger, Christian
Gronberg, Henrik
Hall, Per
Hattersley, Andrew T
Hengstenberg, Christian
Hoffman, Wolfgang
Lathrop, G Mark
Salomaa, Veikko
Schreiber, Stefan
Uda, Manuela
Waterworth, Dawn
Wright, Alan F
Assimes, Themistocles L
Barroso, Ines
Hofman, Albert
Mohlke, Karen L
Boomsma, Dorret I
Caulfield, Mark J
Cupples, L Adrienne
Erdmann, Jeanette
Fox, Caroline S
Gudnason, Vilmundur
Gyllensten, Ulf
Harris, Tamara B
Hayes, Richard B
Jarvelin, Marjo-Riitta
Mooser, Vincent
Munroe, Patricia B
Ouwehand, Willem H
Penninx, Brenda W
Pramstaller, Peter P
Quertermous, Thomas
Rudan, Igor
Samani, Nilesh J
Spector, Timothy D
Volzke, Henry
Watkins, Hugh
Wilson, James F
Groop, Leif C
Haritunians, Talin
Hu, Frank B
Kaplan, Robert C
Metspalu, Andres
North, Kari E
Schlessinger, David
Wareham, Nicholas J
Hunter, David J
O'Connell, Jeffrey R
Strachan, David P
Wichmann, H-Erich
Borecki, Ingrid B
van Duijn, Cornelia M
Schadt, Eric E
Thorsteinsdottir, Unnur
Peltonen, Leena
Uitterlinden, Andre G
Visscher, Peter M
Chatterjee, Nilanjan
Loos, Ruth J F
Boehnke, Michael
McCarthy, Mark I
Ingelsson, Erik
Lindgren, Cecilia M
Abecasis, Goncalo R
Stefansson, Kari
Frayling, Timothy M
Hirschhorn, Joel N
eng
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R01-HL087676/HL/NHLBI NIH HHS/
R01-HL087679/HL/NHLBI NIH HHS/
R01-HL087700/HL/NHLBI NIH HHS/
R01-HL088119/HL/NHLBI NIH HHS/
R01-HL59367/HL/NHLBI NIH HHS/
R01-MH059160/MH/NIMH NIH HHS/
R01-MH59565/MH/NIMH NIH HHS/
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R01-MH59586/MH/NIMH NIH HHS/
R01-MH59587/MH/NIMH NIH HHS/
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R01-MH60870/MH/NIMH NIH HHS/
R01-MH60879/MH/NIMH NIH HHS/
R01-MH61675/MH/NIMH NIH HHS/
R01-MH63706/MH/NIMH NIH HHS/
R01-MH67257/MH/NIMH NIH HHS/
R01-MH79469/MH/NIMH NIH HHS/
R01-MH81800/MH/NIMH NIH HHS/
RC2 HG005581/HG/NHGRI NIH HHS/
RC2 HG005581-02/HG/NHGRI NIH HHS/
RL1 MH083268/MH/NIMH NIH HHS/
RL1 MH083268-05/MH/NIMH NIH HHS/
RL1-MH083268/MH/NIMH NIH HHS/
T32 DK007191/DK/NIDDK NIH HHS/
T32-HG00040/HG/NHGRI NIH HHS/
U01 CA049449/CA/NCI NIH HHS/
U01 CA049449-21/CA/NCI NIH HHS/
U01 CA098233/CA/NCI NIH HHS/
U01 CA098233-08/CA/NCI NIH HHS/
U01 DK062370/DK/NIDDK NIH HHS/
U01 DK062370-08/DK/NIDDK NIH HHS/
U01 DK062418/DK/NIDDK NIH HHS/
U01 GM074518/GM/NIGMS NIH HHS/
U01 GM074518-05/GM/NIGMS NIH HHS/
U01 HG004399/HG/NHGRI NIH HHS/
U01 HG004399-02/HG/NHGRI NIH HHS/
U01 HG004402/HG/NHGRI NIH HHS/
U01 HG004402-02/HG/NHGRI NIH HHS/
U01 HG005214/HG/NHGRI NIH HHS/
U01 HG005214-02/HG/NHGRI NIH HHS/
U01 HL069757/HL/NHLBI NIH HHS/
U01 HL069757-10/HL/NHLBI NIH HHS/
U01 HL072515/HL/NHLBI NIH HHS/
U01 HL072515-06/HL/NHLBI NIH HHS/
U01 HL080295/HL/NHLBI NIH HHS/
U01 HL080295-04/HL/NHLBI NIH HHS/
U01 HL084729/HL/NHLBI NIH HHS/
U01 HL084729-03/HL/NHLBI NIH HHS/
U01 HL084756/HL/NHLBI NIH HHS/
U01 HL084756-03/HL/NHLBI NIH HHS/
U01 MH079469/MH/NIMH NIH HHS/
U01 MH079469-03/MH/NIMH NIH HHS/
U01 MH079470/MH/NIMH NIH HHS/
U01 MH079470-03/MH/NIMH NIH HHS/
U01-CA098233/CA/NCI NIH HHS/
U01-GM074518/GM/NIGMS NIH HHS/
U01-HG004399/HG/NHGRI NIH HHS/
U01-HG004402/HG/NHGRI NIH HHS/
U01-HL080295/HL/NHLBI NIH HHS/
U01-HL084756/HL/NHLBI NIH HHS/
U01-HL72515/HL/NHLBI NIH HHS/
U01-MH79469/MH/NIMH NIH HHS/
U01-MH79470/MH/NIMH NIH HHS/
U54-RR020278/RR/NCRR NIH HHS/
UL1-RR025005/RR/NCRR NIH HHS/
Z01-AG00675/AG/NIA NIH HHS/
Z01-AG007380/AG/NIA NIH HHS/
Z01-HG000024/HG/NHGRI NIH HHS/
Cancer Research UK/United Kingdom
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
England
2010/10/01 06:00
Nature. 2010 Oct 14;467(7317):832-8. doi: 10.1038/nature09410. Epub 2010 Sep 29.
Keywords: Body Height/*genetics, Chromosomes, Human, Pair 3/genetics, Genetic Loci/*genetics, Genetic Predisposition to Disease/genetics, Genome, Human/*genetics, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways/*genetics, Multifactorial Inheritance/genetics, Phenotype, Polymorphism, Single Nucleotide/*genetics
DOI: 10.1038/nature09410
ISSN: 0028-0836
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2010 Macmillan Publishers Limited
Deposited On: 18 Jan 2016 01:37
Last Modified: 15 Feb 2016 23:24

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