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

  title={Defining the role of common variation in the genomic and biological architecture of adult human height},
  author={Andrew R. Wood and T{\~o}nu Esko and Jian Yang and Sailaja Vedantam and Tune H. Pers and Stefan Gustafsson and Audrey Y. Chu and Karol Estrada and Jian’an Luan and Zolt{\'a}n Kutalik and Najaf Amin and Martin L Buchkovich and Damien C. Croteau-Chonka and Felix R. Day and Yanan Duan and Tove Fall and Rudolf S. N. Fehrmann and Teresa Ferreira and Anne U. Jackson and Juha Karjalainen and Ken Sin Lo and Adam E. Locke and Reedik M{\"a}gi and Evelin Mihailov and Eleonora Porcu and Joshua C. Randall and Andr{\'e} Scherag and Anna A. E. Vinkhuyzen and Harm-Jan Westra and Thomas W. Winkler and Tsegaselassie Workalemahu and Jing Hua Zhao and Devin M Absher and Eva Albrecht and Denise Anderson and Jeffrey Baron and Marian Beekman and Ayşe Demirkan and Georg B. Ehret and Bjarke Feenstra and Mary F. Feitosa and Krista Fischer and Ross M Fraser and Anuj Goel and Jian Gong and Anne E. Justice and Stavroula Kanoni and Marcus Edi Kleber and Kati Kristiansson and Unhee Lim and Vaneet S. Lotay and Julian C. Lui and Massimo Mangino and Irene Mateo Leach and Carolina Medina-Gomez and Mike A. Nalls and Dale R. Nyholt and Cameron Palmer and Dorota Pasko and Sonali Pechlivanis and Inga Prokopenko and Janina S. Ried and Stephan Ripke and Dmitry Shungin and Alena Stan{\vc}{\'a}kov{\'a} and Rona J. Strawbridge and Yun Ju Sung and Toshiko Tanaka and Alexander Teumer and Stella Trompet and Sander W. van der Laan and Jessica van Setten and Jana V. van Vliet-Ostaptchouk and Zhaoming Wang and Loic Yengo and Weihua Zhang and Uzma Afzal and Johan {\"A}rnl{\"o}v and Gillian M. Arscott and Stefania Bandinelli and Amy Barrett and Claire Bellis and Amanda Bennett and Christian Berne and Matthias Bl{\"u}her and Jennifer L. Bolton and Yvonne B{\"o}ttcher and Heather Allison Boyd and Marcel Bruinenberg and Brendan M. Buckley and Steven Buyske and Ida Henriette Caspersen and Peter S. Chines and Robert J. Clarke and Simone Claudi-Boehm and Matthew N. Cooper and E. Warwick Daw and Pim A. de Jong and Joris Deelen and Graciela E. Delgado and Joshua Charles Denny and Rosalie A. M. Dhonukshe-Rutten and Maria Dimitriou and Alex S. F. Doney and Marcus D{\"o}rr and Niina Eklund and Elodie Eury and Lasse Folkersen and Melissa E. Garcia and Frank Geller and Vilmantas Giedraitis and Alan S. Go and Harald Grallert and Tanja B. Grammer and J{\"u}rgen Gr{\"a}ssler and Henrik Gr{\"o}nberg and Lisette C.P.G.M. de Groot and Christopher J. Groves and Jeff Haessler and Per Hall and Toomas Haller and Göran Hallmans and Anke Hannemann and Catharina A. Hartman and Maija Hassinen and Caroline Hayward and Nancy L. Heard-Costa and Quinta Helmer and Gibran Hemani and Anjali K. Henders and Hans L. Hillege and Mark A. Hlatky and Wolfgang U. Hoffmann and Per Hoffmann and Oddgeir Lingaas Holmen and Jeanine J. Houwing-Duistermaat and Thomas Illig and Aaron Isaacs and Alan L James and Janina M. Jeff and Berit Johansen and {\AA}sa Johansson and Jennifer D. Jolley and Thorhildur Juliusdottir and Juhani M Junttila and Abel N. Kho and Leena Kinnunen and Norman Klopp and Thomas Kocher and Wolfgang Kratzer and Peter Lichtner and Lars Lind and Jaana Lindstr{\"o}m and St{\'e}phane Lobbens and Mattias Lorentzon and Yingchang Lu and Valeriya Lyssenko and Patrik K. E. Magnusson and Anubha Mahajan and Marc P Maillard and Wendy L McArdle and Colin A Mckenzie and Stela McLachlan and Paul J. McLaren and Cristina Menni and Sigrun Merger and Lili Milani and Alireza Moayyeri and Keri L. Monda and Mario A. Morken and Gabriele M{\"u}ller and Martina M{\"u}ller-Nurasyid and Arthur William Musk and Narisu Narisu and Matthias Nauck and Ilja Maria Nolte and Markus M. N{\"o}then and Laticia Oozageer and Stefan Pilz and Nigel William Rayner and Frida Renstrom and Neil R. Robertson and Lynda M Rose and Ronan Roussel and Serena Sanna and Hubert Scharnagl and Salome Scholtens and Fredrick R. Schumacher and Heribert Schunkert and Robert A. Scott and Joban S. Sehmi and Thomas Seufferlein and Jianxin Shi and Karri Silventoinen and Johannes H. Smit and Albert Vernon Smith and Joanna Smolonska and Alice V. Stanton and Kathleen E. Stirrups and David J. Stott and Heather M. Stringham and Johan Sundstr{\"o}m and Morris A. Swertz and Ann-Christine Syv{\"a}nen and Bamidele O. Tayo and Gudmar Thorleifsson and Jonathan P. Tyrer and Suzanne C. van Dijk and Natasja M. van Schoor and Nathalie van der Velde and Diana van Heemst and Floor V. A. van Oort and Sita H. Vermeulen and Niek Verweij and Judith M. Vonk and Lindsay L. Waite and Melanie Waldenberger and Roman Wennauer and Lynne R Wilkens and Christina Willenborg and Tom Wilsgaard and Mary K. Wojczynski and Andrew Wong and Alan F. Wright and Qunyuan Zhang and Dominique Arveiler and Stephan J. L. Bakker and John P. Beilby and Richard N. Bergman and S. Bergmann and Reiner Biffar and John Blangero and Dorret I. Boomsma and Stefan R. Bornstein and Pascal Bovet and Paolo Brambilla and Morris J. Brown and Harry Campbell and Mark J. Caulfield and Aravinda Chakravarti and Rory Collins and Francis S. Collins and Dana C. Crawford and L. Adrienne Cupples and John Danesh and Ulf de Faire and Hester M. den Ruijter and Raimund Erbel and Jeanette Erdmann and Johan Gunnar Eriksson and Martin Farrall and Ele Ferrannini and Jean Ferri{\`e}res and Ian Ford and Nita G. Forouhi and Terrence E Forrester and Ron T. Gansevoort and Pablo V. Gejman and Christian Gieger and Alain Golay and Omri Gottesman and Vilmundur G. Gudnason and Ulf Gyllensten and David W. Haas and Alistair S. Hall and Tamara B. Harris and Andrew T. Hattersley and Andrew C. Heath and Christian Hengstenberg and Andrew A. Hicks and Lucia A. Hindorff and Aroon D. Hingorani and Albert Hofman and G Kees Hovingh and Steve E. Humphries and Steven C. Hunt and Elina Hypponen and Kevin B. Jacobs and Marjo-Riitta Jarvelin and Pekka Jousilahti and Antti M. Jula and Jaakko A Kaprio and John J Kastelein and Manfred Kayser and Frank Kee and Sirkka Keinanen-Kiukaanniemi and Lambertus A.L.M. Kiemeney and Jaspal S Kooner and Charles L. Kooperberg and Seppo Koskinen and Peter Kovacs and Aldi T. Kraja and Meena Kumari and Johanna Kuusisto and Timo A. Lakka and Claudia Langenberg and Lo{\"i}c Le Marchand and Terho Lehtim{\"a}ki and Sara Lupoli and Pamela A. F. Madden and Satu M{\"a}nnist{\"o} and Paolo Manunta and Andr{\'e} Marette and Tara Cox Matise and Barbara McKnight and Thomas Meitinger and Frans L. Moll and Grant W. Montgomery and Andrew D. Morris and Andrew P. Morris and Jeffrey C. Murray and Mari Nelis and Claes Ohlsson and Albertine J. Oldehinkel and Ken K. Ong and Willem Hendrik Ouwehand and Gerard Pasterkamp and Annette Peters and Peter Paul Pramstaller and Jackie F. Price and Lu Qi and Olli T. Raitakari and Tuomo Rankinen and D. C. Rao and Treva K. Rice and Marylyn DeRiggi Ritchie and Igor Rudan and Veikko V Salomaa and Nilesh J. Samani and Jouko Saramies and Mark A. Sarzynski and Peter E H Schwarz and Sylvain Sebert and Peter S Sever and Alan R. Shuldiner and Juha P. Sinisalo and Valgerdur Steinthorsdottir and Ronald P Stolk and Jean-Claude Tardif and Anke Tönjes and Angelo Tremblay and Elena Tremoli and Jarmo R. K. Virtamo and Marie-Claude Vohl and Philippe Amouyel and Folkert W. Asselbergs and Themistocles L. Assimes and Murielle Bochud and Bernhard Otto Boehm and Eric Boerwinkle and Erwin P. Bottinger and Claude Bouchard and Stéphane Cauchi and John C Chambers and Stephen J. Chanock and Richard S. Cooper and Paul I. W. de Bakker and George V. Dedoussis and Luigi Ferrucci and Paul W. Franks and Philippe Froguel and Leif C. Groop and Christopher A. Haiman and Anders Hamsten and M. Geoffrey Hayes and Jennie Hui and David J. Hunter and Kristian Hveem and Johan Wouter Jukema and Robert C. Kaplan and Mika Kivimaki and Diana Kuh and Markku Laakso and Yongmei Liu and Nicholas G. Martin and Winfried M{\"a}rz and Mads Melbye and Susanne Moebus and Patricia B. Munroe and Inger Nj{\o}lstad and Ben A. Oostra and Colin N. A. Palmer and Nancy L. Pedersen and Markus Perola and Louis P{\'e}russe and Ulrike Peters and Joseph E. Powell and Christine Power and Thomas Quertermous and Rainer Rauramaa and Eva Reinmaa and Paul M. Ridker and Fernando Rivadeneira and Jerome I. Rotter and Timo E. Saaristo and Danish Saleheen and David Schlessinger and Pieternella E Slagboom and Harold Snieder and Tim D. Spector and Konstantin Strauch and Michael Stumvoll and Jaakko Tuomilehto and Matti Uusitupa and Pim van der Harst and Henry V{\"o}lzke and Mark Walker and Nicholas J. Wareham and Hugh C. Watkins and Heinz-Erich Wichmann and James F. Wilson and Pieter Zanen and Panos Deloukas and Iris M. Heid and Cecilia M. Lindgren and Karen L. Mohlke and Elizabeth K. Speliotes and Unnur Thorsteinsd{\'o}ttir and In{\^e}s Barroso and Caroline S Fox and Kari E. North and David P. Strachan and Jacques S. Beckmann and Sonja I. Berndt and Michael Boehnke and Ingrid B. Borecki and Mark I. McCarthy and Andres Metspalu and K{\'a}ri Stef{\'a}nsson and Andr{\'e} G. Uitterlinden and Cornelia M. van Duijn and Lude Franke and Cristen J. Willer and Alkes L. Price and Guillaume Lettre and Ruth J. F. Loos and Michael N. Weedon and Erik Ingelsson and Jeffrey R. O’Connell and Gonçalo R. Abecasis and Daniel I. Chasman and Michael Goddard and Peter M. Visscher and Joel N. Hirschhorn and Timothy M. Frayling},
  journal={Nature genetics},
  pages={1173 - 1186}
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… 

A saturated map of common genetic variants associated with human height

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Intergenic GWAS SNPs are key components of the spatial and regulatory network for human growth.

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Revisiting the Population Genetics of Human Height

  • P. Rotwein
  • Biology
    Journal of the Endocrine Society
  • 2020
A larger-scale analysis of individuals from diverse backgrounds will be necessary to ensure a full and accurate understanding of the genetic underpinnings of human height throughout the world, and additional studies will be needed to discern the biochemical and molecular mechanisms governing the physiological processes that explain how these variant proteins might selectively impact the biology of the growth plate.

Identification of novel genetic variants associated with short stature in a Baka Pygmies population

The results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.

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This study empirically demonstrates that CH plays an important role in adult height and may explain a proportion of its “missing heritability”, and raises promising expectations for other highly polygenic complex traits to explain missing heritability identifiable through CH-like associations.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

98 loci are identified, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance, and novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height.



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Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height.

An analytic approach may be applied to GWA studies for other common polygenic traits and diseases, thus providing a new general strategy to identify causative genes within GWA loci and to translate genetic associations into mechanistic biological insights.

Genome partitioning of genetic variation for complex traits using common SNPs

The results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.

Common SNPs explain a large proportion of the heritability for human height

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An expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

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The Metabochip and its component SNP sets are described and evaluated, its performance in capturing variation across the allele-frequency spectrum is evaluated, solutions to methodological challenges commonly encountered in its analysis are described, and its performance as a platform for genotype imputation is evaluated.

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