Dataset Information

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

ABSTRACT: 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/?-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.

SUBMITTER: Wood AR

PROVIDER: S-EPMC4250049 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

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

Nature genetics 20141005 11

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 gen ...[more]

PMID: 25282103

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Project description:Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?<?0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Dataset Information

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

Publications

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

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