Rare and low-frequency coding variants alter human adult height
Eirini Marouli, Mariaelisa Graff, Carolina Medina‐Gómez, Ken Sin Lo, Andrew R. Wood, Troels R. Kjær, Rebecca S. Fine, Yingchang Lu, Claudia Schurmann, Heather M. Highland, Sina Rüeger, Guðmar Þorleifsson, Anne E. Justice, David Lamparter, Kathleen Stirrups, Valérie Turcot, Kristin L. Young, Thomas W. Winkler, Tõnu Esko, Tugce Karaderi, Adam E. Locke, Nicholas G. D. Masca, Maggie C. Y. Ng, Poorva Mudgal, Manuel A. Rivas, Sailaja Vedantam, Anubha Mahajan, Xiuqing Guo, Gonçalo R. Abecasis, Katja K.H. Aben, Linda S. Adair, Dewan S Alam, Eva Albrecht, Kristine H. Allin, Matthew Allison, Philippe Amouyel, Emil V. R. Appel, Dominique Arveiler, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Bernhard Banas, Lia E. Bang, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blueher, H. Boeing, Eric Boerwinkle, Carsten A. Boeger, Lori L. Bonnycastle, Jette Bork‐Jensen, Michiel L. Bots, Erwin P. Böttinger, Donald W. Bowden, Ivan Brandslund, Gerome Breen, Murray H. Brilliant, Linda Broer, Amber 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 Cuéllar-Partida, John Danesh, Gail Davies, Paul I. W. de Bakker, Gert J. de Borst, Simon de Denus, Mark de Groot, Renée de Mutsert, Ian J. Deary, George Dedoussis, Ellen W. Demerath, Anneke I. den Hollander, Joe Dennis, Emanuele Di Angelantonio, Fotios Drenos, Mengmeng Du, Alison M. Dunning, Douglas F. Easton, Tapani Ebeling, Todd L. Edwards, Patrick T. Ellinor, Paul Elliott, Εvangelos Εvangelou, Aliki‐Eleni Farmaki, Jessica D. Faul, Mary F. Feitosa, Shuang Feng, Ele Ferrannini, Maurizio Ferrario, Jean Ferrières, José C. Florez, Ian Ford, Myriam Fornage, Paul W. Franks, Ruth Frikke‐Schmidt, Tessel E. Galesloot, Wei Liang 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 Guðnason, 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 M. M. Howson, Carel B. Hoyng, Paul L. Huang, Kristian Hveem, M. Arfan Ikram, Erik Ingelsson, Anne Jackson, Jan‐Håkan Jansson, Gail P. Jarvik, Gorm Boje 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 L. R. Kardia, Fredrik Karpe, Frank Kee, Renske Keeman, Lambertus A. Kiemeney, Hidetoshi Kitajima, Kirsten B. Kluivers, Thomas D. Kocher, Pirjo Komulainen, Jukka Kontto, Jaspal S. Kooner, Charles Kooperberg, Péter Kovács, 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, Ching‐Ti Liu, Artitaya Lophatananon, Jian’an Luan, Steven A. Lubitz, Leo‐Pekka Lyytikäinen, David A. Mackey, Pamela A. F. 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, Nauck Matthias, Christopher P. Nelson, Matt J. Neville, Sune F. Nielsen, Kjell Nikus, Pål R. Njølstad, Børge G. Nordestgaard, Ιωάννα Ντάλλα, Jeffrey R. O’Connel, Heikki Oksa, Loes M. Olde Loohuis, Roel A. Ophoff, Katharine R. Owen, Chris J. Packard, Sandosh Padmanabhan, Nicholette D. Palmer, Gerard Pasterkamp, Aniruddh P. Patel, Alison Pattie, Oluf Pedersen, Peggy Peissig, Gina M. Peloso, Craig E. Pennell, Markus Perola, James A. Perry, John R. B. Perry, Thomas N. Person, Ailith Pirie, Ozren Polašek, Daniëlle Posthuma, Olli T. Raitakari, Asif Al 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 H. Shah, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S. Small, Albert V. Smith, Jennifer A. Smith, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, John M. Starr, Valgerður Steinthórsdóttir, Heather M. Stringham, Michael Stümvoll, Praveen Surendran, Leen M. ‘t Hart, Katherine E. Tansey, Jean‐Claude Tardif, Kent D. Taylor, Alexander Teumer, Deborah J. Thompson, Unnur Þorsteinsdóttir, Betina H. Thuesen, Anke Toenjes, Gerard Tromp, Stella Trompet, Emmanouil Tsafantakis, J Tuomilehto, Anne Tybjærg‐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, Véronique Vitart, Thomas 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, Wei Zhao, Wei Zhao, Zheng He, Wei Zhou, Jerome I. Rotter, Michael Boehnke, Sekar Kathiresan, Mark I. McCarthy, Cristen J. Willer, Kāri Stefánsson, 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 J. F. Loos, Timothy M. Frayling, Joel N. Hirschhorn, Panos Deloukas, Guillaume Lettre
Carolina Digital Repository (University of North Carolina at Chapel Hill)
January 1, 2017
Cited by 154Open Access
Abstract
<p>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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.</p>
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