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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-10

AUTHORS

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

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. More... »

PAGES

832

Journal

TITLE

Nature

ISSUE

7317

VOLUME

467

Author Affiliations

  • University of Exeter
  • Wageningen University & Research
  • University of Montreal
  • National Institutes of Health
  • University of Michigan–Ann Arbor
  • Broad Institute
  • Wellcome Centre for Human Genetics
  • Massachusetts General Hospital
  • Wellcome Sanger Institute
  • King's College London
  • QIMR Berghofer Medical Research Institute
  • deCODE Genetics (Iceland)
  • Boston University School of Medicine
  • Harvard University
  • University of Iceland
  • McGill University
  • University Hospital Regensburg
  • Department of Environment, Land, Water and Planning
  • Montreal Heart Institute
  • Norwegian University of Science and Technology
  • Erasmus University Medical Center
  • Washington University in St. Louis
  • University of Tartu
  • Swiss Institute of Bioinformatics
  • University of Oxford
  • HudsonAlpha Institute for Biotechnology
  • University of Greifswald
  • University of Washington
  • Western General Hospital
  • VU University Amsterdam
  • Leidos (United States)
  • Stanford University
  • University of North Carolina at Chapel Hill
  • University of Zagreb
  • University of Lübeck
  • University of Cambridge
  • Karolinska Institute
  • Wake Forest University
  • National Institute for Health and Welfare
  • Imperial College London
  • University of Western Australia
  • Royal National Hospital for Rheumatic Diseases
  • University of Maryland, Baltimore
  • MSD (United States)
  • University of Oulu
  • University of Gothenburg
  • Ludwig Maximilian University of Munich
  • Boston University
  • University of Milan
  • University of Leicester
  • Lund University
  • University of Leeds
  • University of Edinburgh
  • Vita-Salute San Raffaele University
  • University of Glasgow
  • NorthShore University HealthSystem
  • Vaasa Central Hospital
  • University of California Los Angeles
  • University of Sassari
  • Sir Charles Gairdner Hospital
  • Uppsala University
  • Leipzig University
  • Finnish Institute of Occupational Health
  • Genome Institute of Singapore
  • University of Helsinki
  • University of Split
  • Rechts der Isar Hospital
  • McMaster University
  • Amgen (United States)
  • Helsinki University Central Hospital
  • Cedars-Sinai Medical Center
  • Cambridge Centre
  • VU University Medical Center
  • Lapland Central Hospital
  • University of Bristol
  • University Hospital of Lausanne
  • University of Southern California
  • National Human Genome Research Institute
  • Radboud University Nijmegen Medical Centre
  • Icelandic Heart Association
  • University of California, San Francisco
  • Tampere University Hospital
  • University of Tampere
  • University of Mississippi Medical Center
  • Turku University Hospital
  • University of Lausanne
  • Baltimore VA Medical Center
  • Seinäjoen Keskussairaala
  • Leiden University Medical Center
  • The University of Texas Health Science Center at Houston
  • Centre National de Génotypage
  • GlaxoSmithKline (United States)
  • Institute of Metabolic Science
  • National Heart Lung and Blood Institute
  • New York University Langone Medical Center
  • University Medical Center Groningen
  • Glenfield Hospital
  • Albert Einstein College of Medicine
  • National Institute on Aging
  • University College London
  • Klinikum der Universität München
  • Sage Bionetworks
  • Churchill Hospital
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature09410

    DOI

    http://dx.doi.org/10.1038/nature09410

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037714920

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/20881960


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