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Leif Groop

Leif Groop

Principal investigator

Leif Groop

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

Author

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

Summary, in English

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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2010

Language

English

Pages

832-838

Publication/Series

Nature

Volume

467

Issue

7317

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 0028-0836