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 Karaderi,
Adam 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 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 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 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,
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,
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,
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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 J F 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.