• DOI:10.1038/nature09410
• Corpus ID: 4408491

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

@article{LangoAllen2010HundredsOV,
  title={Hundreds of variants clustered in genomic loci and biological pathways affect human height},
  author={Hana Lango Allen and Karol Estrada and Guillaume Lettre and Sonja I. Berndt and Michael N. Weedon and Fernando Rivadeneira and Cristen J. Willer and Anne U. Jackson and Sailaja Vedantam and Soumya Raychaudhuri and Teresa Ferreira and Andrew R. Wood and Robert J. Weyant and Ayellet V. Segr{\`e} and Elizabeth K. Speliotes and Eleanor Wheeler and Nicole Soranzo and Ju-Hyun Park and Jian Yang and Daniel Fannar Gudbjartsson and Nancy L. Heard-Costa and Joshua C. Randall and Lu Qi and Albert Vernon Smith and Reedik M{\"a}gi and Tomi Pastinen and Liming Liang and Iris M. Heid and Jian’an Luan and Gudmar Thorleifsson and Thomas W. Winkler and Michael Goddard and Ken Sin Lo and Cameron Palmer and Tsegaselassie Workalemahu and Yurii S. Aulchenko and {\AA}sa Johansson and M. Carola Zillikens and Mary F. Feitosa and T{\~o}nu Esko and Toby Johnson and Shamika Ketkar and Peter Kraft and Massimo Mangino and Inga Prokopenko and Devin M Absher and Eva Albrecht and Florian D. Ernst and Nicole L. Glazer and Caroline Hayward and Jouke- Jan Hottenga and Kevin B. Jacobs and Joshua W. Knowles and Zolt{\'a}n Kutalik and Keri L. Monda and Ozren Pola{\vs}ek and Michael H. Preuss and Nigel William Rayner and Neil R. Robertson and Valgerdur Steinthorsdottir and Jonathan P. Tyrer and Benjamin F. Voight and Fredrik Wiklund and Jianfeng Xu and Jing Hua Zhao and Dale R. Nyholt and Niina Pellikka and Markus Perola and John R. B. Perry and Ida Surakka and Mari-Liis Tammesoo and Elisabeth Altmaier and Najaf Amin and Thor Aspelund and Tushar R. Bhangale and Gabrielle Boucher and Daniel I. Chasman and Constance Chen and Lachlan J. M. Coin and Matthew N. Cooper and Anna L. Dixon and Quince D. Gibson and Elin Grundberg and Ke Hao and M. Juhani Junttila and Lee M. Kaplan and Johannes Kettunen and Inke Regina K{\"o}nig and Tony Kwan and Robert Lawrence and Douglas F. Levinson and Mattias Lorentzon and Barbara McKnight and Andrew P. Morris and Martina M{\"u}ller and Julius S. Ngwa and Shaun M Purcell and Suzanne Rafelt and Rany M. Salem and Erika Salvi and Serena Sanna and Jianxin Shi and Ulla Sovio and John R. Thompson and Michael C. Turchin and Liesbeth Vandenput and Dominique J. Verlaan and Veronique Vitart and Charles White and Andreas Ziegler and Peter Almgren and Anthony J. Balmforth and Harry Campbell and Lorena Citterio and Alessandro De Grandi and Anna F. Dominiczak and Jubao Duan and Paul Elliott and Roberto Elos{\'u}a and Johan Gunnar Eriksson and Nelson B. Freimer and Eco J. C. de Geus and Nicola Glorioso and Shen Haiqing and A-L. Hartikainen and Aki Samuli Havulinna and Andrew A. Hicks and Jennie Hui and Wilmar Igl and Thomas Illig and Antti M. Jula and Eero Kajantie and Tuomas O. Kilpel{\"a}inen and Markku Koiranen and Ivana Kol{\vc}i{\'c} and Seppo Koskinen and Peter Kovacs and Jaana Laitinen and Jianjun Liu and Marja-Liisa Lokki and Ana Maru{\vs}i{\'c} and Andrea Maschio and Thomas Meitinger and Antonella Mulas and Guillaume Par{\'e} and Alex N. Parker and John F. Peden and Astrid Petersmann and Irene Pichler and Kirsi H. Pietil{\"a}inen and Anneli Pouta and Martin Ridderstr{\aa}le and Jerome I. Rotter and Jennifer G. Sambrook and Alan R. Sanders and Carsten Oliver Schmidt and Juha P. Sinisalo and Jan H Smit and Heather M. Stringham and G. Bragi Walters and Elisabeth Wid{\'e}n and Sarah H. Wild and Gonneke Willemsen and Laura Zagato and Lina Zgaga and Paavo J. Zitting and Helene Alavere and Martin Farrall and Wendy L. McArdle and Mari Nelis and Marjolein J. Peters and Samuli Ripatti and Joyce B.J. van Meurs and Katja K. H. Aben and Kristin G. Ardlie and Jacques S. Beckmann and John P. Beilby and Richard N. Bergman and S. Bergmann and Francis S. Collins and Daniele Cusi and Martin den Heijer and Gudny Eiriksdottir and Pablo V. Gejman and Alistair S. Hall and Anders Hamsten and Heikki Veli Huikuri and Carlos Iribarren and Mika K{\"a}h{\"o}nen and Jaakko A Kaprio and Sekar Kathiresan and Lambertus A. Kiemeney and Thomas Kocher and Lenore J. Launer and Terho Lehtim{\"a}ki and Olle Melander and Thomas H. Mosley and Arthur William Musk and Markku S Nieminen and Christopher J. O’Donnell and Claes Ohlsson and Ben A. Oostra and Lyle J. Palmer and Olli T. Raitakari and Paul M. Ridker and John D. Rioux and Aila M. Rissanen and Carlo Rivolta and Heribert Schunkert and Alan R. Shuldiner and David S. Siscovick and Michael Stumvoll and Anke Tönjes and Jaakko Tuomilehto and Gert-Jan van Ommen and Jorma S.A. Viikari and Andrew C. Heath and Nicholas G. Martin and Grant W. Montgomery and Michael A. Province and Manfred Kayser and Alice M Arnold and Larry D. Atwood and Eric Boerwinkle and Stephen J. Chanock and Panos Deloukas and Christian Gieger and Henrik Gr{\"o}nberg and Per Hall and Andrew T. Hattersley and Christian Hengstenberg and Wolfgang Hoffman and G. Mark Lathrop and Veikko V Salomaa and Stefan Schreiber and Manuela Uda and Dawn M. Waterworth and Alan F. Wright and Themistocles L. Assimes and In{\^e}s Barroso and Albert Hofman and Karen L. Mohlke and Dorret I. Boomsma and Mark J. Caulfield and L. Adrienne Cupples and Jeanette Erdmann and Caroline S. Fox and Vilmundur G. Gudnason and Ulf Gyllensten and Tamara B. Harris and Richard B. Hayes and Marjo-Riitta Jarvelin and Vincent Mooser and Patricia B. Munroe and Willem Hendrik Ouwehand and Brenda W.J.H. Penninx and Peter Paul Pramstaller and Thomas Quertermous and Igor Rudan and Nilesh J. Samani and Tim D. Spector and Henry V{\"o}lzke and Hugh C. Watkins and James F. Wilson and Leif C. Groop and Talin Haritunians and Frank B. Hu and Robert C. Kaplan and Andres Metspalu and Kari E. North and David Schlessinger and Nicholas J. Wareham and David J. Hunter and Jeffrey R. O’Connell and David P. Strachan and Heinz-Erich Wichmann and Ingrid B. Borecki and Cornelia M. van Duijn and Eric E. Schadt and Unnur Thorsteinsd{\'o}ttir and Leena Peltonen and Andr{\'e} G. Uitterlinden and Peter M. Visscher and Nilanjan Chatterjee and Ruth J. F. Loos and Michael Boehnke and Mark I. McCarthy and Erik Ingelsson and Cecilia M. Lindgren and Gonçalo R. Abecasis and K{\'a}ri Stef{\'a}nsson and Timothy M. Frayling and Joel N. Hirschhorn},
  journal={Nature},
  year={2010},
  volume={467},
  pages={832 - 838}
}

• H. Lango Allen, K. Estrada, +290 authors J. Hirschhorn
• Published 10 August 2010
• Biology
• Nature

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.