Defining the role of common variation in the genomic and biological architecture of adult human height.

Authors:
Dr Julian C Lui, PhD
Dr Julian C Lui, PhD
National Institutes of Child Health and Human Development
Pediatric Endocrinology / Cartilage
Bethesda, MD | United States
Dr Anubha Mahajan, PhD
Dr Anubha Mahajan, PhD
Wellcome Trust Centre for Human Genetics, University of Oxford
UK
Dr Marc Maillard, PhD,PharmD
Dr Marc Maillard, PhD,PharmD
Lausanne University Hospital
Head of Laboratory
Lausanne | Switzerland
Andrew R Wood Tonu Esko Jian Yang Sailaja Vedantam Tune H Pers Stefan Gustafsson Audrey Y Chu Karol Estrada Jian'an Luan Zoltán Kutalik Najaf Amin Martin L Buchkovich Damien C Croteau-Chonka Felix R Day Yanan Duan Tove Fall Rudolf Fehrmann Teresa Ferreira Anne U Jackson Juha Karjalainen Ken Sin Lo Adam E Locke Reedik Mägi Evelin Mihailov Eleonora Porcu Joshua C Randall André Scherag Anna A E Vinkhuyzen Harm-Jan Westra Thomas W Winkler Tsegaselassie Workalemahu Jing Hua Zhao Devin Absher Eva Albrecht Denise Anderson Jeffrey Baron Marian Beekman Ayse Demirkan Georg B Ehret Bjarke Feenstra Mary F Feitosa Krista Fischer Ross M Fraser Anuj Goel Jian Gong Anne E Justice Stavroula Kanoni Marcus E Kleber Kati Kristiansson Unhee Lim Vaneet Lotay Massimo Mangino Irene Mateo Leach Carolina Medina-Gomez Michael A Nalls Dale R Nyholt Cameron D Palmer Dorota Pasko Sonali Pechlivanis Inga Prokopenko Janina S Ried Stephan Ripke Dmitry Shungin Alena Stancáková Rona J Strawbridge Yun Ju Sung Toshiko Tanaka Alexander Teumer Stella Trompet Sander W van der Laan Jessica van Setten Jana V Van Vliet-Ostaptchouk Zhaoming Wang Loïc Yengo Weihua Zhang Uzma Afzal Johan Arnlöv Gillian M Arscott Stefania Bandinelli Amy Barrett Claire Bellis Amanda J Bennett Christian Berne Matthias Blüher Jennifer L Bolton Yvonne Böttcher Heather A Boyd Marcel Bruinenberg Brendan M Buckley Steven Buyske Ida H Caspersen Peter S Chines Robert Clarke Simone Claudi-Boehm Matthew Cooper E Warwick Daw Pim A De Jong Joris Deelen Graciela Delgado Josh C Denny Rosalie Dhonukshe-Rutten Maria Dimitriou Alex S F Doney Marcus Dörr Niina Eklund Elodie Eury Lasse Folkersen Melissa E Garcia Frank Geller Vilmantas Giedraitis Alan S Go Harald Grallert Tanja B Grammer Jürgen Gräßler Henrik Grönberg Lisette C P G M de Groot Christopher J Groves Jeffrey Haessler Per Hall Toomas Haller Goran Hallmans Anke Hannemann Catharina A Hartman Maija Hassinen Caroline Hayward Nancy L Heard-Costa Quinta Helmer Gibran Hemani Anjali K Henders Hans L Hillege Mark A Hlatky Wolfgang Hoffmann Per Hoffmann Oddgeir Holmen Jeanine J Houwing-Duistermaat Thomas Illig Aaron Isaacs Alan L James Janina Jeff Berit Johansen Åsa Johansson Jennifer Jolley Thorhildur Juliusdottir Juhani Junttila Abel N Kho Leena Kinnunen Norman Klopp Thomas Kocher Wolfgang Kratzer Peter Lichtner Lars Lind Jaana Lindström Stéphane Lobbens Mattias Lorentzon Yingchang Lu Valeriya Lyssenko Patrik K E Magnusson Wendy L McArdle Colin A McKenzie Stela McLachlan Paul J McLaren Cristina Menni Sigrun Merger Lili Milani Alireza Moayyeri Keri L Monda Mario A Morken Gabriele Müller Martina Müller-Nurasyid Arthur W Musk Narisu Narisu Matthias Nauck Ilja M Nolte Markus M Nöthen Laticia Oozageer Stefan Pilz Nigel W Rayner Frida Renstrom Neil R Robertson Lynda M Rose Ronan Roussel Serena Sanna Hubert Scharnagl Salome Scholtens Fredrick R Schumacher Heribert Schunkert Robert A Scott Joban Sehmi Thomas Seufferlein Jianxin Shi Karri Silventoinen Johannes H Smit Albert Vernon Smith Joanna Smolonska Alice V Stanton Kathleen Stirrups David J Stott Heather M Stringham Johan Sundström Morris A Swertz Ann-Christine Syvänen Bamidele O Tayo Gudmar Thorleifsson Jonathan P Tyrer Suzanne van Dijk Natasja M van Schoor Nathalie van der Velde Diana van Heemst Floor V A van Oort Sita H Vermeulen Niek Verweij Judith M Vonk Lindsay L Waite Melanie Waldenberger Roman Wennauer Lynne R Wilkens Christina Willenborg Tom Wilsgaard Mary K Wojczynski Andrew Wong Alan F Wright Qunyuan Zhang Dominique Arveiler Stephan J L Bakker John Beilby Richard N Bergman Sven Bergmann Reiner Biffar John Blangero Dorret I Boomsma Stefan R Bornstein Pascal Bovet Paolo Brambilla Morris J Brown Harry Campbell Mark J Caulfield Aravinda Chakravarti Rory Collins Francis S Collins Dana C Crawford L Adrienne Cupples John Danesh Ulf de Faire Hester M den Ruijter Raimund Erbel Jeanette Erdmann Johan G Eriksson Martin Farrall Ele Ferrannini Jean Ferrières Ian Ford Nita G Forouhi Terrence Forrester Ron T Gansevoort Pablo V Gejman Christian Gieger Alain Golay Omri Gottesman Vilmundur Gudnason Ulf Gyllensten David W Haas Alistair S Hall Tamara B Harris Andrew T Hattersley Andrew C Heath Christian Hengstenberg Andrew A Hicks Lucia A Hindorff Aroon D Hingorani Albert Hofman G Kees Hovingh Steve E Humphries Steven C Hunt Elina Hypponen Kevin B Jacobs Marjo-Riitta Jarvelin Pekka Jousilahti Antti M Jula Jaakko Kaprio John J P Kastelein Manfred Kayser Frank Kee Sirkka M Keinanen-Kiukaanniemi Lambertus A Kiemeney Jaspal S Kooner Charles Kooperberg Seppo Koskinen Peter Kovacs Aldi T Kraja Meena Kumari Johanna Kuusisto Timo A Lakka Claudia Langenberg Loic Le Marchand Terho Lehtimäki Sara Lupoli Pamela A F Madden Satu Männistö Paolo Manunta André Marette Tara C Matise Barbara McKnight Thomas Meitinger Frans L Moll Grant W Montgomery Andrew D Morris Andrew P Morris Jeffrey C Murray Mari Nelis Claes Ohlsson Albertine J Oldehinkel Ken K Ong Willem H Ouwehand Gerard Pasterkamp Annette Peters Peter P Pramstaller Jackie F Price Lu Qi Olli T Raitakari Tuomo Rankinen D C Rao Treva K Rice Marylyn Ritchie Igor Rudan Veikko Salomaa Nilesh J Samani Jouko Saramies Mark A Sarzynski Peter E H Schwarz Sylvain Sebert Peter Sever Alan R Shuldiner Juha Sinisalo Valgerdur Steinthorsdottir Ronald P Stolk Jean-Claude Tardif Anke Tönjes Angelo Tremblay Elena Tremoli Jarmo Virtamo Marie-Claude Vohl Philippe Amouyel Folkert W Asselbergs Themistocles L Assimes Murielle Bochud Bernhard O Boehm Eric Boerwinkle Erwin P Bottinger Claude Bouchard Stéphane Cauchi John C Chambers Stephen J Chanock Richard S Cooper Paul I W de Bakker George Dedoussis Luigi Ferrucci Paul W Franks Philippe Froguel Leif C Groop Christopher A Haiman Anders Hamsten M Geoffrey Hayes Jennie Hui David J Hunter Kristian Hveem J Wouter Jukema Robert C Kaplan Mika Kivimaki Diana Kuh Markku Laakso Yongmei Liu Nicholas G Martin Winfried März Mads Melbye Susanne Moebus Patricia B Munroe Inger Njølstad Ben A Oostra Colin N A Palmer Nancy L Pedersen Markus Perola Louis Pérusse Ulrike Peters Joseph E Powell Chris Power Thomas Quertermous Rainer Rauramaa Eva Reinmaa Paul M Ridker Fernando Rivadeneira Jerome I Rotter Timo E Saaristo Danish Saleheen David Schlessinger P Eline Slagboom Harold Snieder Tim D Spector Konstantin Strauch Michael Stumvoll Jaakko Tuomilehto Matti Uusitupa Pim van der Harst Henry Völzke Mark Walker Nicholas J Wareham Hugh Watkins H-Erich Wichmann James F Wilson Pieter Zanen Panos Deloukas Iris M Heid Cecilia M Lindgren Karen L Mohlke Elizabeth K Speliotes Unnur Thorsteinsdottir Inês Barroso Caroline S Fox Kari E North David P Strachan Jacques S Beckmann Sonja I Berndt Michael Boehnke Ingrid B Borecki Mark I McCarthy Andres Metspalu Kari Stefansson André G Uitterlinden Cornelia M van Duijn Lude Franke Cristen J Willer Alkes L Price Guillaume Lettre Ruth J F Loos Michael N Weedon Erik Ingelsson Jeffrey R O'Connell Goncalo R Abecasis Daniel I Chasman Michael E Goddard Peter M Visscher Joel N Hirschhorn Timothy M Frayling

Nat Genet 2014 Nov 5;46(11):1173-86. Epub 2014 Oct 5.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

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November 2014
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