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

Lango Allen, Hana and Estrada, Karol and Lettre, Guillaume and Berndt, Sonja I. and Weedon, Michael N. and Rivadeneira, Fernando and Willer, Cristen J. and Jackson, Anne U. and Vedantam, Sailaja and Raychaudhuri, Soumya and Ferreira, Teresa and Wood, Andrew R. and Weyant, Robert J. and Segrè, Ayellet V. and Speliotes, Elizabeth K. and Wheeler, Eleanor and Soranzo, Nicole and Park, Ju-Hyun and Yang, Jian and Gudbjartsson, Daniel and Heard-Costa, Nancy L. and Randall, Joshua C. and Qi, Lu and Vernon Smith, Albert and Mägi, Reedik and Pastinen, Tomi and Liang, Liming and Heid, Iris M. and Luan, Jian'an and Thorleifsson, Gudmar and Winkler, Thomas W. and Goddard, Michael E. and Sin Lo, Ken and Palmer, Cameron and Workalemahu, Tsegaselassie and Aulchenko, Yurii S. and Johansson, Asa and Zillikens, M. Carola and Feitosa, Mary F. and Esko, Tõnu and Johnson, Toby and Ketkar, Shamika and Kraft, Peter and Mangino, Massimo and Prokopenko, Inga and Absher, Devin and Albrecht, Eva and Ernst, Florian and Glazer, Nicole L. and Hayward, Caroline and Hottenga, Jouke-Jan and Jacobs, Kevin B. and Knowles, Joshua W. and Kutalik, Zoltán and Monda, Keri L. and Polasek, Ozren and Preuss, Michael and Rayner, Nigel W. and Robertson, Neil R. and Steinthorsdottir, Valgerdur and Tyrer, Jonathan P. and Voight, Benjamin F. and Wiklund, Fredrik and Xu, Jianfeng and Zhao, Jing Hua and Nyholt, Dale R. and Pellikka, Niina and Perola, Markus and Perry, John R. B. and Surakka, Ida and Tammesoo, Mari-Liis and Altmaier, Elizabeth L. and Amin, Najaf and Aspelund, Thor and Bhangale, Tushar and Boucher, Gabrielle and Chasman, Daniel I. and Chen, Constance and Coin, Lachlan and Cooper, Matthew N. and Dixon, Anna L. and Gibson, Quince and Grundberg, Elin and Hao, Ke and Juhani Junttila, M. and Kaplan, Lee M. and Kettunen, Johannes and König, Inke R. and Kwan, Tony and Lawrence, Robert W. and Levinson, Douglas F. and Lorentzon, Mattias and McKnight, Barbara and Morris, Andrew P. and Müller, Martina and Suh Ngwa, Julius and Purcell, Shaun and Rafelt, Suzanne and Salem, Rany M. and Salvi, Erika and Sanna, Serena and Shi, Jianxin and Sovio, Ulla and Thompson, John R. and Turchin, Michael C. and Vandenput, Liesbeth and Verlaan, Dominique J. and Vitart, Veronique and White, Charles C. and Ziegler, Andreas and Almgren, Peter and Balmforth, Anthony J. and Campbell, Harry and Citterio, Lorena and De Grandi, Alessandro and Dominiczak, Anna and Duan, Jubao and Elliott, Paul and Elosua, Roberto and Eriksson, Johan G. and Freimer, Nelson B. and Geus, Eco J. C. and Glorioso, Nicola and Haiqing, Shen and Hartikainen, Anna-Liisa and Havulinna, Aki S. and Hicks, Andrew A. and Hui, Jennie and Igl, Wilmar and Illig, Thomas and Jula, Antti and Kajantie, Eero and Kilpeläinen, Tuomas O. and Koiranen, Markku and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Laitinen, Jaana and Liu, Jianjun and Lokki, Marja-Liisa and Marusic, Ana and Maschio, Andrea and Meitinger, Thomas and Mulas, Antonella and Paré, Guillaume and Parker, Alex N. and Peden, John F. and Petersmann, Astrid and Pichler, Irene and Pietiläinen, Kirsi H. and Pouta, Anneli and Ridderstråle, Martin and Rotter, Jerome I. and Sambrook, Jennifer G. and Sanders, Alan R. and Schmidt, Carsten Oliver and Sinisalo, Juha and Smit, Jan H. and Stringham, Heather M. and Bragi Walters, G. and Widen, Elisabeth and Wild, Sarah H. and Willemsen, Gonneke and Zagato, Laura and Zgaga, Lina and Zitting, Paavo and Alavere, Helene and Farrall, Martin and McArdle, Wendy L. and Nelis, Mari and Peters, Marjolein J. and Ripatti, Samuli and van Meurs, Joyce B. J. and Aben, Katja K. and Ardlie, Kristin G. and Beckmann, Jacques S. and Beilby, John P. and Bergman, Richard N. and Bergmann, Sven and Collins, Francis S. and Cusi, Daniele and den Heijer, Martin and Eiriksdottir, Gudny and Gejman, Pablo V. and Hall, Alistair S. and Hamsten, Anders and Huikuri, Heikki V. and Iribarren, Carlos and Kähönen, Mika and Kaprio, Jaakko and Kathiresan, Sekar and Kiemeney, Lambertus and Kocher, Thomas and Launer, Lenore J. and Lehtimäki, Terho and Melander, Olle and Mosley, Tom H. and Musk, Arthur W. and Nieminen, Markku S. and O'Donnell, Christopher J. and Ohlsson, Claes and Oostra, Ben and Palmer, Lyle J. and Raitakari, Olli and Ridker, Paul M. and Rioux, John D. and Rissanen, Aila and Rivolta, Carlo and Schunkert, Heribert and Shuldiner, Alan R. and Siscovick, David S. and Stumvoll, Michael and Tönjes, Anke and Tuomilehto, Jaakko and van Ommen, Gert-Jan and Viikari, Jorma and Heath, Andrew C. and Martin, Nicholas G. and Montgomery, Grant W. and Province, Michael A. and Kayser, Manfred and Arnold, Alice M. and Atwood, Larry D. and Boerwinkle, Eric and Chanock, Stephen J. and Deloukas, Panos and Gieger, Christian and Grönberg, Henrik and Hall, Per and Hattersley, Andrew T. and Hengstenberg, Christian and Hoffman, Wolfgang and Lathrop, G. Mark and Salomaa, Veikko and Schreiber, Stefan and Uda, Manuela and Waterworth, Dawn and Wright, Alan F. and Assimes, Themistocles L. and Barroso, Inês and Hofman, Albert and Mohlke, Karen L. and Boomsma, Dorret I. and Caulfield, Mark J. and Cupples, L. Adrienne and Erdmann, Jeanette and Fox, Caroline S. and Gudnason, Vilmundur and Gyllensten, Ulf and Harris, Tamara B. and Hayes, Richard B. and Jarvelin, Marjo-Riitta and Mooser, Vincent and Munroe, Patricia B. and Ouwehand, Willem H. and Penninx, Brenda W. and Pramstaller, Peter P. and Quertermous, Thomas and Rudan, Igor and Samani, Nilesh J. and Spector, Timothy D. and Völzke, Henry and Watkins, Hugh and Wilson, James F. and Groop, Leif C. and Haritunians, Talin and Hu, Frank B. and Kaplan, Robert C. and Metspalu, Andres and North, Kari E. and Schlessinger, David and Wareham, Nicholas J. and Hunter, David J. and O'Connell, Jeffrey R. and Strachan, David P. and Wichmann, H-Erich and Borecki, Ingrid B. and van Duijn, Cornelia M. and Schadt, Eric E. and Thorsteinsdottir, Unnur and Peltonen, Leena and Uitterlinden, André G. and Visscher, Peter M. and Chatterjee, Nilanjan and Loos, Ruth J. F. and Boehnke, Michael and McCarthy, Mark I. and Ingelsson, Erik and Lindgren, Cecilia M. and Abecasis, Gonçalo R. and Stefansson, Kari and Frayling, Timothy M. and Hirschhorn, Joel 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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Official URL: https://edoc.unibas.ch/81792/

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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.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Springer Nature
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Mar 2021 12:42
Deposited On:10 Feb 2021 08:21

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