Hundreds of variants clustered in genomic loci and biological pathways affect human height

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


title = "Hundreds of variants clustered in genomic loci and biological pathways affect human height",
abstract = "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(1), 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(2,3). 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.",
author = "Allen, {Hana Lango} and Karol Estrada and Guillaume Lettre and Berndt, {Sonja I.} and Weedon, {Michael N.} and Fernando Rivadeneira and Willer, {Cristen J.} and Jackson, {Anne U.} and Sailaja Vedantam and Soumya Raychaudhuri and Teresa Ferreira and Wood, {Andrew R.} and Weyant, {Robert J.} and Segre, {Ayellet V.} and Speliotes, {Elizabeth K.} and Eleanor Wheeler and Nicole Soranzo and Ju-Hyun Park and Jian Yang and Daniel Gudbjartsson and Heard-Costa, {Nancy L.} and Randall, {Joshua C.} and Lu Qi and Smith, {Albert Vernon} and Reedik Maegi and Tomi Pastinen and Liming Liang and Heid, {Iris M.} and Jian'an Luan and Gudmar Thorleifsson and Winkler, {Thomas W.} and Goddard, {Michael E.} and Lo, {Ken Sin} and Cameron Palmer and Tsegaselassie Workalemahu and Aulchenko, {Yurii S.} and Asa Johansson and Zillikens, {M. Carola} and Feitosa, {Mary F.} and Tonu Esko and Toby Johnson and Shamika Ketkar and Peter Kraft and Massimo Mangino and Inga Prokopenko and Devin Absher and Eva Albrecht and Florian Ernst and Glazer, {Nicole L.} and Caroline Hayward and Jouke-Jan Hottenga and Jacobs, {Kevin B.} and Knowles, {Joshua W.} and Zoltan Kutalik and Monda, {Keri L.} and Ozren Polasek and Michael Preuss and Rayner, {Nigel W.} and Robertson, {Neil R.} and Valgerdur Steinthorsdottir and Tyrer, {Jonathan P.} and Voight, {Benjamin F.} and Fredrik Wiklund and Jianfeng Xu and Zhao, {Jing Hua} and Nyholt, {Dale R.} and Niina Pellikka and Markus Perola and Perry, {John R. B.} and Ida Surakka and Mari-Liis Tammesoo and Altmaier, {Elizabeth L.} and Najaf Amin and Thor Aspelund and Tushar Bhangale and Gabrielle Boucher and Chasman, {Daniel I.} and Constance Chen and Lachlan Coin and Cooper, {Matthew N.} and Dixon, {Anna L.} and Quince Gibson and Elin Grundberg and Ke Hao and Junttila, {M. Juhani} and Kaplan, {Lee M.} and Johannes Kettunen and Koenig, {Inke R.} and Tony Kwan and Lawrence, {Robert W.} and Levinson, {Douglas F.} and Mattias Lorentzon and Barbara McKnight and Morris, {Andrew P.} and Martina Mueller and Ngwa, {Julius Suh} and Shaun Purcell and Suzanne Rafelt and Salem, {Rany M.} and Erika Salvi and Serena Sanna and Jianxin Shi and Ulla Sovio and Thompson, {John R.} and Turchin, {Michael C.} and Liesbeth Vandenput and Verlaan, {Dominique J.} and Veronique Vitart and White, {Charles C.} and Andreas Ziegler and Peter Almgren and Balmforth, {Anthony J.} and Harry Campbell and Lorena Citterio and {De Grandi}, Alessandro and Anna Dominiczak and Jubao Duan and Paul Elliott and Roberto Elosua and Eriksson, {Johan G.} and Freimer, {Nelson B.} and Geus, {Eco J. C.} and Nicola Glorioso and Shen Haiqing and Anna-Liisa Hartikainen and Havulinna, {Aki S.} and Hicks, {Andrew A.} and Jennie Hui and Wilmar Igl and Thomas Illig and Antti Jula and Eero Kajantie and Kilpelaeinen, {Tuomas O.} and Markku Koiranen and Ivana Kolcic and Seppo Koskinen and Peter Kovacs and Jaana Laitinen and Jianjun Liu and Marja-Liisa Lokki and Ana Marusic and Andrea Maschio and Thomas Meitinger and Antonella Mulas and Guillaume Pare and Parker, {Alex N.} and Peden, {John F.} and Astrid Petersmann and Irene Pichler and Pietilainen, {Kirsi H.} and Anneli Pouta and Martin Riddertrale and Rotter, {Jerome I.} and Sambrook, {Jennifer G.} and Sanders, {Alan R.} and Schmidt, {Carsten Oliver} and Juha Sinisalo and Smit, {Jan H.} and Stringham, {Heather M.} and Walters, {G. Bragi} and Elisabeth Widen and Wild, {Sarah H.} and Gonneke Willemsen and Laura Zagato and Lina Zgaga and Paavo Zitting and Helene Alavere and Martin Farrall and McArdle, {Wendy L.} and Mari Nelis and Peters, {Marjolein J.} and Samuli Ripatti and {vVan Meurs}, {Joyce B. J.} and Aben, {Katja K.} and Ardlie, {Kristin G.} and Beckmann, {Jacques S.} and Beilby, {John P.} and Bergman, {Richard N.} and Sven Bergmann and Collins, {Francis S.} and Daniele Cusi and {den Heijer}, Martin and Gudny Eiriksdottir and Gejman, {Pablo V.} and Hall, {Alistair S.} and Anders Hamsten and Huikuri, {Heikki V.} and Carlos Iribarren and Mika Kahonen and Jaakko Kaprio and Sekar Kathiresan and Lambertus Kiemeney and Thomas Kocher and Launer, {Lenore J.} and Terho Lehtimaki and Olle Melander and Mosley, {Tom H., Jr.} and Musk, {Arthur W.} and Nieminen, {Markku S.} and O'Donnell, {Christopher J.} and Claes Ohlsson and Ben Oostra and Palmer, {Lyle J.} and Olli Raitakari and Ridker, {Paul M.} and Rioux, {John D.} and Aila Rissanen and Carlo Rivolta and Heribert Schunkert and Shuldiner, {Alan R.} and Siscovick, {David S.} and Michael Stumvoll and Anke Toenjes and Jaakko Tuomilehto and {van Ommen}, Gert-Jan and Jorma Viikari and Heath, {Andrew C.} and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Province, {Michael A.} and Manfred Kayser and Arnold, {Alice M.} and Atwood, {Larry D.} and Eric Boerwinkle and Chanock, {Stephen J.} and Panos Deloukas and Christian Gieger and Henrik Gronberg and Per Hall and Hattersley, {Andrew T.} and Christian Hengstenberg and Wolfgang Hoffman and Lathrop, {G. Mark} and Veikko Salomaa and Stefan Schreiber and Manuela Uda and Dawn Waterworth and Wright, {Alan F.} and Assimes, {Themistocles L.} and Ines Barroso and Albert Hofman and Mohlke, {Karen L.} and Boomsma, {Dorret I.} and Caulfield, {Mark J.} and Cupples, {L. Adrienne} and Jeanette Erdmann and Fox, {Caroline S.} and Vilmundur Gudnason and Ulf Gyllensten and Harris, {Tamara B.} and Hayes, {Richard B.} and Marjo-Ritta Jarvelin and Vincent Mooser and Munroe, {Patricia B.} and Ouwehand, {Willem H.} and Penninx, {Brenda W.} and Pramstaller, {Peter P.} and Thomas Quertermous and Igor Rudan and Samani, {Nilesh J.} and Spector, {Timothy D.} and Henry Voelzke and Hugh Watkins and Wilson, {James F.} and Leif Groop and Talin Haritunians and Hu, {Frank B.} and Kaplan, {Robert C.} and Andres Metspalu and North, {Kari E.} and David Schlessinger and Wareham, {Nicholas J.} and Hunter, {David J.} and O'Connell, {Jeffrey R.} and Strachan, {David P.} and Schadt, {H. -Erich} and Unnur Thorsteinsdottir and Leena Peltonen and Uitterlinden, {Andre G.} and Visscher, {Peter M.} and Nilanjan Chatterjee and Loos, {Ruth J. F.} and Michael Boehnke and McCarthy, {Mark I.} and Erik Ingelsson and Lindgren, {Cecilia M.} and Abecasis, {Goncalo R.} and Kari Stefansson and Frayling, {Timothy M.} and Hirschhorn, {Joel N.}",
year = "2010",
doi = "10.1038/nature09410",
language = "English",
volume = "467",
pages = "832--838",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7317",