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

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; Procardis Consortium

doi:10.1038/nature09410

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

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

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, …

Nature (London), Vol.467(7317), pp.832-838

14/10/2010

DOI: https://doi.org/10.1038/nature09410

PMID: 20881960

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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.

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Title: Hundreds of variants clustered in genomic loci and biological pathways affect human height
Creators: Hana Lango Allen - University of Exeter
Karol Estrada - Erasmus University Rotterdam
Guillaume Lettre - Montreal Heart Institute
Sonja I. Berndt - National Cancer Institute
Michael N. Weedon - University of Exeter
Fernando Rivadeneira - Erasmus University Rotterdam
Cristen J. Willer - University of Michigan–Ann Arbor
Anne U. Jackson - University of Michigan–Ann Arbor
Sailaja Vedantam - Boston Children's Hospital
Soumya Raychaudhuri - Broad Institute
Teresa Ferreira - University of Oxford
Andrew R. Wood - University of Exeter
Robert J. Weyant - University of Michigan–Ann Arbor
Ayellet V. Segre - Broad Institute
Elizabeth K. Speliotes - Broad Institute
Eleanor Wheeler - Wellcome Sanger Institute
Nicole Soranzo - Wellcome Sanger Institute
Ju-Hyun Park - Natl Canc Inst, Natl Inst Hlth, Divis Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA
Jian Yang - QIMR Berghofer Medical Research Institute
Daniel Gudbjartsson - deCODE Genet, IS-101 Reykjavik, Iceland
Nancy L. Heard-Costa - Boston University
Joshua C. Randall - Wellcome Centre for Human Genetics
Lu Qi - Harvard University
Albert Vernon Smith - Icelandic Heart Association
Reedik Maegi - University of Oxford
Tomi Pastinen - McGill University and Génome Québec Innovation Centre
Liming Liang - Harvard University
Iris M. Heid - University of Regensburg
Jian'an Luan - The Metropolitan Opera
Gudmar Thorleifsson - deCODE Genet, IS-101 Reykjavik, Iceland
Thomas W. Winkler - University of Regensburg
Michael E. Goddard - University of Melbourne
Ken Sin Lo - Montreal Heart Institute
Cameron Palmer - Boston Children's Hospital
Tsegaselassie Workalemahu - Harvard University
Yurii S. Aulchenko - Netherlands Consortium for Healthy Ageing
Asa Johansson - Uppsala University
M. Carola Zillikens - Erasmus University Rotterdam
Mary F. Feitosa - Washington University in St. Louis
Tonu Esko - University of Tartu
Toby Johnson - University of Lausanne
Shamika Ketkar - Washington University in St. Louis
Peter Kraft - Harvard University
Massimo Mangino - King's College London
Inga Prokopenko - Wellcome Centre for Human Genetics
Devin Absher - HudsonAlpha Institute for Biotechnology
Eva Albrecht - Helmholtz Zentrum München
Florian Ernst - Universität Greifswald
Nicole L. Glazer - University of Washington
Caroline Hayward - Western General Hospital
Jouke-Jan Hottenga - University of Amsterdam
Kevin B. Jacobs - Science Applications International Corporation
Joshua W. Knowles - Stanford University
Zoltan Kutalik - University of Lausanne
Keri L. Monda - University of North Carolina at Chapel Hill
Ozren Polasek - University of Zagreb
Michael Preuss - University of Lübeck
Nigel W. Rayner - University of Oxford
Neil R. Robertson - University of Oxford
Valgerdur Steinthorsdottir - deCODE Genet, IS-101 Reykjavik, Iceland
Jonathan P. Tyrer - University of Cambridge
Benjamin F. Voight - Massachusetts Institute of Technology
Fredrik Wiklund - Karolinska Institutet
Jianfeng Xu - Wake Forest University
Jing Hua Zhao - The Metropolitan Opera
Dale R. Nyholt - QIMR Berghofer Medical Research Institute
Niina Pellikka - University of Helsinki
Markus Perola - University of Helsinki
John R. B. Perry - Peninsula College of Medicine and Dentistry
Ida Surakka - Institute for Molecular Medicine Finland
Mari-Liis Tammesoo - University of Tartu
Elizabeth L. Altmaier - Broad Institute
Najaf Amin - Erasmus University Rotterdam
Thor Aspelund - Icelandic Heart Association
Tushar Bhangale - University of Washington
Gabrielle Boucher - Montreal Heart Institute
Daniel I. Chasman - Brigham and Women's Hospital
Constance Chen - Harvard University
Lachlan Coin - Imperial College London
Matthew N. Cooper - University of Western Australia
Anna L. Dixon - University of Bath
Quince Gibson - University of Maryland, Baltimore
Elin Grundberg - Wellcome Sanger Institute
Ke Hao - Rosetta Stone
M. Juhani Junttila - University of Oulu
Lee M. Kaplan - Massachusetts General Hospital
Johannes Kettunen - University of Helsinki
Inke R. Koenig - University of Lübeck
Tony Kwan - McGill University and Génome Québec Innovation Centre
Robert W. Lawrence - University of Western Australia
Douglas F. Levinson - Stanford University
Mattias Lorentzon - University of Gothenburg
Barbara McKnight - University of Washington
Andrew P. Morris - Wellcome Centre for Human Genetics
Martina Mueller - Helmholtz Zentrum München
Julius Suh Ngwa - Boston University
Shaun Purcell - Center for Human Genetics
Suzanne Rafelt - Glenfield Hospital
Rany M. Salem - Broad Institute
Erika Salvi - University of Milan
Procardis Consortium
Publication Details: Nature (London), Vol.467(7317), pp.832-838
Publisher: Springer Nature
Number of pages: 7
Date published: 14/10/2010
Grant note: Torsten and Ragnar Soderberg's Foundation Finska Lakaresallskapet 014-93-015 / Research Institute for Diseases in the Elderly Support for Science Funding programme German Ministry of Cultural Affairs Vastra Gotaland Foundation ALF/LUA Gothenburg National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Swedish Research Council 050-060-810 / Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging
Identifiers: 99929034002346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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