Rare and low-frequency coding variants alter human adult height View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-02-01

AUTHORS

Eirini Marouli, Mariaelisa Graff, Carolina Medina-Gomez, Ken Sin Lo, Andrew R Wood, Troels R Kjaer, Rebecca S Fine, Yingchang Lu, Claudia Schurmann, Heather M Highland, Sina Rüeger, Gudmar Thorleifsson, Anne E Justice, David Lamparter, Kathleen E Stirrups, Valérie Turcot, Kristin L Young, Thomas W Winkler, Tõnu Esko, Tugce Karaderi, Adam E Locke, Nicholas GD Masca, Maggie CY Ng, Poorva Mudgal, Manuel A Rivas, Sailaja Vedantam, Anubha Mahajan, Xiuqing Guo, Goncalo Abecasis, Katja K Aben, Linda S Adair, Dewan S Alam, Eva Albrecht, Kristine H Allin, Matthew Allison, Philippe Amouyel, Emil V Appel, Dominique Arveiler, Folkert W Asselbergs, Paul L Auer, Beverley Balkau, Bernhard Banas, Lia E Bang, Marianne Benn, Sven Bergmann, Lawrence F Bielak, Matthias Blüher, Heiner Boeing, Eric Boerwinkle, Carsten A Böger, Lori L Bonnycastle, Jette Bork-Jensen, Michiel L Bots, Erwin P Bottinger, Donald W Bowden, Ivan Brandslund, Gerome Breen, Murray H Brilliant, Linda Broer, Amber A Burt, Adam S Butterworth, David J Carey, Mark J Caulfield, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y Chu, Massimiliano Cocca, Francis S Collins, James P Cook, Janie Corley, Jordi Corominas Galbany, Amanda J Cox, Gabriel Cuellar-Partida, John Danesh, Gail Davies, Paul IW de Bakker, Gert J. de Borst, Simon de Denus, Mark CH de Groot, Renée de Mutsert, Ian J Deary, George Dedoussis, Ellen W Demerath, Anneke I den Hollander, Joe G Dennis, Emanuele Di Angelantonio, Fotios Drenos, Mengmeng Du, Alison M Dunning, Douglas F Easton, Tapani Ebeling, Todd L Edwards, Patrick T Ellinor, Paul Elliott, Evangelos Evangelou, Aliki-Eleni Farmaki, Jessica D Faul, Mary F Feitosa, Shuang Feng, Ele Ferrannini, Marco M Ferrario, Jean Ferrieres, Jose C Florez, Ian Ford, Myriam Fornage, Paul W Franks, Ruth Frikke-Schmidt, Tessel E Galesloot, Wei Gan, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Ayush Giri, Giorgia Girotto, Scott D Gordon, Penny Gordon-Larsen, Mathias Gorski, Niels Grarup, Megan L. Grove, Vilmundur Gudnason, Stefan Gustafsson, Torben Hansen, Kathleen Mullan Harris, Tamara B Harris, Andrew T Hattersley, Caroline Hayward, Liang He, Iris M Heid, Kauko Heikkilä, Øyvind Helgeland, Jussi Hernesniemi, Alex W Hewitt, Lynne J Hocking, Mette Hollensted, Oddgeir L Holmen, G. Kees Hovingh, Joanna MM Howson, Carel B Hoyng, Paul L Huang, Kristian Hveem, M. Arfan Ikram, Erik Ingelsson, Anne U Jackson, Jan-Håkan Jansson, Gail P Jarvik, Gorm B Jensen, Min A Jhun, Yucheng Jia, Xuejuan Jiang, Stefan Johansson, Marit E Jørgensen, Torben Jørgensen, Pekka Jousilahti, J Wouter Jukema, Bratati Kahali, René S Kahn, Mika Kähönen, Pia R Kamstrup, Stavroula Kanoni, Jaakko Kaprio, Maria Karaleftheri, Sharon LR Kardia, Fredrik Karpe, Frank Kee, Renske Keeman, Lambertus A Kiemeney, Hidetoshi Kitajima, Kirsten B Kluivers, Thomas Kocher, Pirjo Komulainen, Jukka Kontto, Jaspal S Kooner, Charles Kooperberg, Peter Kovacs, Jennifer Kriebel, Helena Kuivaniemi, Sébastien Küry, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Timo A Lakka, Ethan M Lange, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Eric B Larson, I-Te Lee, Terho Lehtimäki, Cora E Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Honghuang Lin, Li-An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Yeheng Liu, Yongmei Liu, Artitaya Lophatananon, Jian'an Luan, Steven A Lubitz, Leo-Pekka Lyytikäinen, David A Mackey, Pamela AF Madden, Alisa K Manning, Satu Männistö, Gaëlle Marenne, Jonathan Marten, Nicholas G Martin, Angela L Mazul, Karina Meidtner, Andres Metspalu, Paul Mitchell, Karen L Mohlke, Dennis O Mook-Kanamori, Anna Morgan, Andrew D Morris, Andrew P Morris, Martina Müller-Nurasyid, Patricia B Munroe, Mike A Nalls, Matthias Nauck, Christopher P Nelson, Matt Neville, Sune F Nielsen, Kjell Nikus, Pål R Njølstad, Børge G Nordestgaard, Ioanna Ntalla, Jeffrey R O'Connel, Heikki Oksa, Loes M Olde Loohuis, Roel A Ophoff, Katharine R Owen, Chris J Packard, Sandosh Padmanabhan, Colin NA Palmer, Gerard Pasterkamp, Aniruddh P Patel, Alison Pattie, Oluf Pedersen, Peggy L Peissig, Gina M Peloso, Craig E Pennell, Markus Perola, James A Perry, John R.B. Perry, Thomas N Person, Ailith Pirie, Ozren Polasek, Danielle Posthuma, Olli T Raitakari, Asif Rasheed, Rainer Rauramaa, Dermot F Reilly, Alex P Reiner, Frida Renström, Paul M Ridker, John D Rioux, Neil Robertson, Antonietta Robino, Olov Rolandsson, Igor Rudan, Katherine S Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J Samani, Kevin Sandow, Yadav Sapkota, Naveed Sattar, Marjanka K Schmidt, Pamela J Schreiner, Matthias B Schulze, Robert A Scott, Marcelo P Segura-Lepe, Svati Shah, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S Small, Albert Vernon Smith, Jennifer A Smith, Lorraine Southam, Timothy D Spector, Elizabeth K Speliotes, John M Starr, Valgerdur Steinthorsdottir, Heather M Stringham, Michael Stumvoll, Praveen Surendran, Leen M ‘t Hart, Katherine E Tansey, Jean-Claude Tardif, Kent D Taylor, Alexander Teumer, Deborah J Thompson, Unnur Thorsteinsdottir, Betina H Thuesen, Anke Tönjes, Gerard Tromp, Stella Trompet, Emmanouil Tsafantakis, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Jonathan P Tyrer, Rudolf Uher, André G Uitterlinden, Sheila Ulivi, Sander W van der Laan, Andries R Van Der Leij, Cornelia M van Duijn, Natasja M van Schoor, Jessica van Setten, Anette Varbo, Tibor V Varga, Rohit Varma, Digna R Velez Edwards, Sita H Vermeulen, Henrik Vestergaard, Veronique Vitart, Thomas F Vogt, Diego Vozzi, Mark Walker, Feijie Wang, Carol A Wang, Shuai Wang, Yiqin Wang, Nicholas J Wareham, Helen R Warren, Jennifer Wessel, Sara M Willems, James G Wilson, Daniel R Witte, Michael O Woods, Ying Wu, Hanieh Yaghootkar, Jie Yao, Pang Yao, Laura M Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Jing Hua Zhao, Wei Zhao, Wei Zhao, He Zheng, Wei Zhou, , , , , , , , , , Jerome I Rotter, Michael Boehnke, Sekar Kathiresan, Mark I McCarthy, Cristen J Willer, Kari Stefansson, Ingrid B Borecki, Dajiang J Liu, Kari E North, Nancy L Heard-Costa, Tune H Pers, Cecilia M Lindgren, Claus Oxvig, Zoltán Kutalik, Fernando Rivadeneira, Ruth JF Loos, Timothy M Frayling, Joel N Hirschhorn, Panos Deloukas, Guillaume Lettre

ABSTRACT

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways. More... »

PAGES

186

References to SciGraph publications

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  • Journal

    TITLE

    Nature

    ISSUE

    7640

    VOLUME

    542

    Author Affiliations

  • Queen Mary University of London
  • University of North Carolina System
  • Erasmus University Medical Center
  • University of Exeter
  • Aarhus University
  • Boston Children's Hospital
  • Icahn School of Medicine at Mount Sinai
  • The University of Texas Health Science Center at Houston
  • Swiss Institute of Bioinformatics
  • University of Lausanne
  • University of Cambridge
  • University of Regensburg
  • University of Tartu
  • Wellcome Centre for Human Genetics
  • Washington University in St. Louis
  • Glenfield Hospital
  • Wake Forest University
  • University of Oxford
  • Harbor–UCLA Medical Center
  • University of Michigan–Ann Arbor
  • Radboud University Nijmegen Medical Centre
  • Helmholtz Zentrum München
  • University of Copenhagen
  • University of California, San Diego
  • Lille 1 University
  • Hôpitaux Universitaires de Strasbourg
  • University College London
  • University of Wisconsin–Milwaukee
  • Centre for research in epidemiology and population health
  • University Hospital Regensburg
  • Leipzig University
  • German Institute of Human Nutrition
  • Baylor College of Medicine
  • National Human Genome Research Institute
  • University Medical Center Utrecht
  • University of Southern Denmark
  • King's College London
  • Marshfield Clinic
  • University of Washington
  • Geisinger Medical Center
  • Imperial College Healthcare NHS Trust
  • Harvard University
  • Sygehus Lillebælt
  • Brigham and Women's Hospital
  • University of Trieste
  • University of Liverpool
  • University of Edinburgh
  • Griffith University
  • QIMR Berghofer Medical Research Institute
  • University of Montreal
  • Utrecht University
  • Leiden University Medical Center
  • Harokopio University
  • University of Minnesota
  • Memorial Sloan Kettering Cancer Center
  • University of Oulu
  • Vanderbilt University
  • Broad Institute
  • Imperial College London
  • University of Ioannina
  • University of Pisa
  • University of Insubria
  • University of Toulouse
  • University of Glasgow
  • Umeå University
  • Sidra Medical and Research Center
  • Uppsala University
  • University of North Carolina at Chapel Hill
  • Icelandic Heart Association
  • National Institutes of Health
  • University of Helsinki
  • University of Bergen
  • University of Tampere
  • University of Tasmania
  • University of Aberdeen
  • Norwegian University of Science and Technology
  • Academic Medical Center
  • Massachusetts General Hospital
  • Stanford University
  • Frederiksberg Hospital
  • University of Southern California
  • Haukeland University Hospital
  • Steno Diabetes Center
  • Capital Region of Denmark
  • National Institute for Health and Welfare
  • Netherlands Heart Institute
  • NIHR Oxford Musculoskeletal Biomedical Research Unit
  • Queen's University Belfast
  • Antoni van Leeuwenhoek Hospital
  • University of Greifswald
  • Kuopion Liikuntalääketieteen Tutkimuslaitos
  • Fred Hutchinson Cancer Research Center
  • Stellenbosch University
  • Centre Hospitalier Universitaire de Nantes
  • IRCCS Materno Infantile Burlo Garofolo
  • University of Eastern Finland
  • Institute of Metabolic Science
  • Group Health Cooperative
  • Chung Shan Medical University
  • University of Alabama at Birmingham
  • Shanghai Institutes for Biological Sciences
  • Boston University School of Medicine
  • Rigshospitalet
  • University of Warwick
  • Wellcome Sanger Institute
  • University of Sydney
  • German Centre for Cardiovascular Research
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases
  • University of Maryland, Baltimore
  • Tampere University Hospital
  • University of California Los Angeles
  • Ninewells Hospital
  • University of Western Australia
  • University of Split
  • Amsterdam Neuroscience
  • University of Turku
  • Kuopio University Hospital
  • MSD (United States)
  • University of Pennsylvania
  • Duke University
  • National University of Singapore
  • University of Bristol
  • University of Iceland
  • King Abdulaziz University
  • Dalhousie University
  • University of Amsterdam
  • VU University Medical Center
  • Lund University
  • Newcastle University
  • Boston University
  • Indiana University of Pennsylvania
  • University of Mississippi Medical Center
  • Memorial University of Newfoundland
  • The University of Texas Southwestern Medical Center
  • Pennsylvania State University
  • Statens Serum Institut
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature21039

    DOI

    http://dx.doi.org/10.1038/nature21039

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1083401652

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28146470


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