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

Artikel i vetenskaplig tidskrift
Författare 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 Segrè
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 Mägi
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
Tõnu 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 König
Tony Kwan
Robert W Lawrence
Douglas F Levinson
Mattias Lorentzon
Barbara McKnight
Andrew P Morris
Martina Muller
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 Kilpeläinen
Markku Koiranen
Ivana Kolcic
Seppo Koskinen
Peter Kovacs
Jaana Laitinen
Jianjun Liu
Marja-Liisa Lokki
Ana Marusic
Andrea Maschio
Thomas Meitinger
Antonella Mulas
Guillaume Paré
Alex N Parker
John F Peden
Astrid Petersmann
Irene Pichler
Kirsi H Pietiläinen
Anneli Pouta
Martin Ridderstråle
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 van 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 Kähönen
Jaakko Kaprio
Sekar Kathiresan
Lambertus Kiemeney
Thomas Kocher
Lenore J Launer
Terho Lehtimäki
Olle Melander
Tom H 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 Tönjes
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 Grönberg
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-Riitta 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 Völzke
Hugh Watkins
James F Wilson
Leif C 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 Wichmann
Ingrid B Borecki
Cornelia M van Duijn
Eric E 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
Gonçalo R Abecasis
Kari Stefansson
Timothy M Frayling
Joel N Hirschhorn
Publicerad i Nature
Volym 467
Nummer/häfte 7317
Sidor 832-8
ISSN 1476-4687
Publiceringsår 2010
Publicerad vid Institutionen för medicin, avdelningen för invärtesmedicin
Centre for Bone and Arthritis Research
Sidor 832-8
Språk en
Länkar dx.doi.org/10.1038/nature09410
Ämnesord Body Height, genetics, Chromosomes, Human, Pair 3, genetics, Genetic Loci, genetics, Genetic Predisposition to Disease, genetics, Genome, Human, genetics, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, genetics, Multifactorial Inheritance, genetics, Phenotype, Polymorphism, Single Nucleotide, genetics
Ämneskategorier Medicinsk genetik

Sammanfattning

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.

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