Rare and low-frequency coding variants alter human adult height

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 KaraderiAdam E. Locke, Nicholas G D Masca, Maggie C Y 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 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 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 I W De Bakker, Gert J. De Borst, Simon De Denus, Mark C H De Groot, Renée De Mutsert, Ian J. Deary, George V. 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 M M 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 L R 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 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, 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 N A Palmer, Gerard Pasterkamp, Aniruddh P. Patel, Alison Pattie, Oluf Pedersen, Peggy L. Peissig, Gina M. Peloso, Craig E. Pennell, Carol A. Wang, MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium

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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.

Original languageEnglish
Pages (from-to)186-190
Number of pages5
JournalNature
Volume542
Issue number7640
DOIs
Publication statusPublished - 9 Feb 2017

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