IDEAS home Printed from https://ideas.repec.org/a/plo/pgen00/1000508.html
   My bibliography  Save this article

Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

Author

Listed:
  • Cecilia M Lindgren
  • Iris M Heid
  • Joshua C Randall
  • Claudia Lamina
  • Valgerdur Steinthorsdottir
  • Lu Qi
  • Elizabeth K Speliotes
  • Gudmar Thorleifsson
  • Cristen J Willer
  • Blanca M Herrera
  • Anne U Jackson
  • Noha Lim
  • Paul Scheet
  • Nicole Soranzo
  • Najaf Amin
  • Yurii S Aulchenko
  • John C Chambers
  • Alexander Drong
  • Jian'an Luan
  • Helen N Lyon
  • Fernando Rivadeneira
  • Serena Sanna
  • Nicholas J Timpson
  • M Carola Zillikens
  • Jing Hua Zhao
  • Peter Almgren
  • Stefania Bandinelli
  • Amanda J Bennett
  • Richard N Bergman
  • Lori L Bonnycastle
  • Suzannah J Bumpstead
  • Stephen J Chanock
  • Lynn Cherkas
  • Peter Chines
  • Lachlan Coin
  • Cyrus Cooper
  • Gabriel Crawford
  • Angela Doering
  • Anna Dominiczak
  • Alex S F Doney
  • Shah Ebrahim
  • Paul Elliott
  • Michael R Erdos
  • Karol Estrada
  • Luigi Ferrucci
  • Guido Fischer
  • Nita G Forouhi
  • Christian Gieger
  • Harald Grallert
  • Christopher J Groves
  • Scott Grundy
  • Candace Guiducci
  • David Hadley
  • Anders Hamsten
  • Aki S Havulinna
  • Albert Hofman
  • Rolf Holle
  • John W Holloway
  • Thomas Illig
  • Bo Isomaa
  • Leonie C Jacobs
  • Karen Jameson
  • Pekka Jousilahti
  • Fredrik Karpe
  • Johanna Kuusisto
  • Jaana Laitinen
  • G Mark Lathrop
  • Debbie A Lawlor
  • Massimo Mangino
  • Wendy L McArdle
  • Thomas Meitinger
  • Mario A Morken
  • Andrew P Morris
  • Patricia Munroe
  • Narisu Narisu
  • Anna Nordström
  • Peter Nordström
  • Ben A Oostra
  • Colin N A Palmer
  • Felicity Payne
  • John F Peden
  • Inga Prokopenko
  • Frida Renström
  • Aimo Ruokonen
  • Veikko Salomaa
  • Manjinder S Sandhu
  • Laura J Scott
  • Angelo Scuteri
  • Kaisa Silander
  • Kijoung Song
  • Xin Yuan
  • Heather M Stringham
  • Amy J Swift
  • Tiinamaija Tuomi
  • Manuela Uda
  • Peter Vollenweider
  • Gerard Waeber
  • Chris Wallace
  • G Bragi Walters
  • Michael N Weedon
  • The Wellcome Trust Case Control Consortium
  • Jacqueline C M Witteman
  • Cuilin Zhang
  • Weihua Zhang
  • Mark J Caulfield
  • Francis S Collins
  • George Davey Smith
  • Ian N M Day
  • Paul W Franks
  • Andrew T Hattersley
  • Frank B Hu
  • Marjo-Riitta Jarvelin
  • Augustine Kong
  • Jaspal S Kooner
  • Markku Laakso
  • Edward Lakatta
  • Vincent Mooser
  • Andrew D Morris
  • Leena Peltonen
  • Nilesh J Samani
  • Timothy D Spector
  • David P Strachan
  • Toshiko Tanaka
  • Jaakko Tuomilehto
  • André G Uitterlinden
  • Cornelia M van Duijn
  • Nicholas J Wareham
  • Hugh Watkins for the PROCARDIS consortia
  • Dawn M Waterworth
  • Michael Boehnke
  • Panos Deloukas
  • Leif Groop
  • David J Hunter
  • Unnur Thorsteinsdottir
  • David Schlessinger
  • H-Erich Wichmann
  • Timothy M Frayling
  • Gonçalo R Abecasis
  • Joel N Hirschhorn
  • Ruth J F Loos
  • Kari Stefansson
  • Karen L Mohlke
  • Inês Barroso
  • Mark I McCarthy for the GIANT consortium

Abstract

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.Author Summary: Here, we describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication (in up to 70,689 individuals) designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR). This work complements parallel efforts that have been successful in defining variants impacting overall adiposity and focuses on the visceral fat accumulation which has particularly strong relationships to metabolic and cardiovascular disease. Our analyses have identified two loci (TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR (all to levels of genome-wide significance). These loci vary in the strength of their associations with overall adiposity, and LYPLAL1 in particular appears to have a specific effect on patterns of fat distribution. All in all, these three loci provide novel insights into human physiology and the development of obesity.

Suggested Citation

  • Cecilia M Lindgren & Iris M Heid & Joshua C Randall & Claudia Lamina & Valgerdur Steinthorsdottir & Lu Qi & Elizabeth K Speliotes & Gudmar Thorleifsson & Cristen J Willer & Blanca M Herrera & Anne U J, 2009. "Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution," PLOS Genetics, Public Library of Science, vol. 5(6), pages 1-13, June.
    • Handle: RePEc:plo:pgen00:1000508
    DOI: 10.1371/journal.pgen.1000508
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000508
    Download Restriction: no
    File URL: https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000508&type=printable
    Download Restriction: no
    File URL: https://libkey.io/10.1371/journal.pgen.1000508?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. B. Devlin & Kathryn Roeder, 1999. "Genomic Control for Association Studies," Biometrics, The International Biometric Society, vol. 55(4), pages 997-1004, December.
    2. Yu-Fang Pei & Jian Li & Lei Zhang & Christopher J Papasian & Hong-Wen Deng, 2008. "Analyses and Comparison of Accuracy of Different Genotype Imputation Methods," PLOS ONE, Public Library of Science, vol. 3(10), pages 1-7, October.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Yvonne V Louwers & Nigel W Rayner & Blanca M Herrera & Lisette Stolk & Christopher J Groves & Thomas M Barber & Andre G Uitterlinden & Stephen Franks & Joop S E Laven & Mark I McCarthy, 2014. "BMI-Associated Alleles Do Not Constitute Risk Alleles for Polycystic Ovary Syndrome Independently of BMI: A Case-Control Study," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-7, January.
    2. Zari Dastani & Marie-France Hivert & Nicholas Timpson & John R B Perry & Xin Yuan & Robert A Scott & Peter Henneman & Iris M Heid & Jorge R Kizer & Leo-Pekka Lyytikäinen & Christian Fuchsberger & Tosh, 2012. "Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals," PLOS Genetics, Public Library of Science, vol. 8(3), pages 1-23, March.
    3. Dorthe S Bille & Karina Banasik & Johanne M Justesen & Camilla H Sandholt & Annelli Sandbæk & Torsten Lauritzen & Torben Jørgensen & Daniel R Witte & Jens-Christian Holm & Torben Hansen & Oluf Pederse, 2011. "Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes," PLOS ONE, Public Library of Science, vol. 6(6), pages 1-7, June.
    4. Nicole M Warrington & Yan Yan Wu & Craig E Pennell & Julie A Marsh & Lawrence J Beilin & Lyle J Palmer & Stephen J Lye & Laurent Briollais, 2013. "Modelling BMI Trajectories in Children for Genetic Association Studies," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-12, January.
    5. Joshua C Randall & Thomas W Winkler & Zoltán Kutalik & Sonja I Berndt & Anne U Jackson & Keri L Monda & Tuomas O Kilpeläinen & Tõnu Esko & Reedik Mägi & Shengxu Li & Tsegaselassie Workalemahu & Mary F, 2013. "Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits," PLOS Genetics, Public Library of Science, vol. 9(6), pages 1-19, June.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Lei Zhang & Yu-Fang Pei & Jian Li & Christopher J Papasian & Hong-Wen Deng, 2009. "Univariate/Multivariate Genome-Wide Association Scans Using Data from Families and Unrelated Samples," PLOS ONE, Public Library of Science, vol. 4(8), pages 1-12, August.
    2. Dominic Holland & Oleksandr Frei & Rahul Desikan & Chun-Chieh Fan & Alexey A Shadrin & Olav B Smeland & V S Sundar & Paul Thompson & Ole A Andreassen & Anders M Dale, 2020. "Beyond SNP heritability: Polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model," PLOS Genetics, Public Library of Science, vol. 16(5), pages 1-30, May.
    3. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    4. Parsa Akbari & Dragana Vuckovic & Luca Stefanucci & Tao Jiang & Kousik Kundu & Roman Kreuzhuber & Erik L. Bao & Janine H. Collins & Kate Downes & Luigi Grassi & Jose A. Guerrero & Stephen Kaptoge & Ju, 2023. "A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Gang Zheng & Zhaohai Li & Mitchell H. Gail & Joseph L. Gastwirth, 2010. "Impact of Population Substructure on Trend Tests for Genetic Case–Control Association Studies," Biometrics, The International Biometric Society, vol. 66(1), pages 196-204, March.
    6. Sandosh Padmanabhan & Olle Melander & Toby Johnson & Anna Maria Di Blasio & Wai K Lee & Davide Gentilini & Claire E Hastie & Cristina Menni & Maria Cristina Monti & Christian Delles & Stewart Laing & , 2010. "Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension," PLOS Genetics, Public Library of Science, vol. 6(10), pages 1-11, October.
    7. Jakris Eu-ahsunthornwattana & E Nancy Miller & Michaela Fakiola & Wellcome Trust Case Control Consortium 2 & Selma M B Jeronimo & Jenefer M Blackwell & Heather J Cordell, 2014. "Comparison of Methods to Account for Relatedness in Genome-Wide Association Studies with Family-Based Data," PLOS Genetics, Public Library of Science, vol. 10(7), pages 1-20, July.
    8. Jianzhong Ma & Christopher I Amos, 2010. "Theoretical Formulation of Principal Components Analysis to Detect and Correct for Population Stratification," PLOS ONE, Public Library of Science, vol. 5(9), pages 1-14, September.
    9. Claire L Simpson & Robert Wojciechowski & Konrad Oexle & Federico Murgia & Laura Portas & Xiaohui Li & Virginie J M Verhoeven & Veronique Vitart & Maria Schache & S Mohsen Hosseini & Pirro G Hysi & Le, 2014. "Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci," PLOS ONE, Public Library of Science, vol. 9(9), pages 1-19, September.
    10. Matthieu Bouaziz & Christophe Ambroise & Mickael Guedj, 2011. "Accounting for Population Stratification in Practice: A Comparison of the Main Strategies Dedicated to Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 6(12), pages 1-13, December.
    11. Aditi Shendre & Howard W Wiener & Marguerite R Irvin & Bradley E Aouizerat & Edgar T Overton & Jason Lazar & Chenglong Liu & Howard N Hodis & Nita A Limdi & Kathleen M Weber & Stephen J Gange & Degui , 2017. "Genome-wide admixture and association study of subclinical atherosclerosis in the Women’s Interagency HIV Study (WIHS)," PLOS ONE, Public Library of Science, vol. 12(12), pages 1-23, December.
    12. Li Shaoyu & Lu Qing & Fu Wenjiang & Romero Roberto & Cui Yuehua, 2009. "A Regularized Regression Approach for Dissecting Genetic Conflicts that Increase Disease Risk in Pregnancy," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 8(1), pages 1-28, October.
    13. Warrington Nicole M. & Tilling Kate & Howe Laura D. & Paternoster Lavinia & Pennell Craig E. & Wu Yan Yan & Briollais Laurent, 2014. "Robustness of the linear mixed effects model to error distribution assumptions and the consequences for genome-wide association studies," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 13(5), pages 1-21, October.
    14. Wang, Linglu & Li, Qizhai & Li, Zhaohai & Zheng, Gang, 2011. "Bayes factors in the presence of population stratification," Statistics & Probability Letters, Elsevier, vol. 81(7), pages 836-841, July.
    15. Boitard Simon & Mangin Brigitte & Azaïs Jean-Marc, 2010. "Asymptotic Distribution of the "Orthogonal" Quantitative Transmission Disequilibrium Test in a Structured Population: Exact Formula," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 9(1), pages 1-25, January.
    16. Ilja M Nolte & Chris Wallace & Stephen J Newhouse & Daryl Waggott & Jingyuan Fu & Nicole Soranzo & Rhian Gwilliam & Panos Deloukas & Irina Savelieva & Dongling Zheng & Chrysoula Dalageorgou & Martin F, 2009. "Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies," PLOS ONE, Public Library of Science, vol. 4(7), pages 1-10, July.
    17. Nick Patterson & Alkes L Price & David Reich, 2006. "Population Structure and Eigenanalysis," PLOS Genetics, Public Library of Science, vol. 2(12), pages 1-20, December.
    18. Ferguson John P. & Palejev Dean, 2014. "P-value calibration for multiple testing problems in genomics," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 13(6), pages 1-15, December.
    19. Tiago C. Silva & Juan I. Young & Lanyu Zhang & Lissette Gomez & Michael A. Schmidt & Achintya Varma & X. Steven Chen & Eden R. Martin & Lily Wang, 2022. "Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    20. Takeshi Nishiyama & Hirohisa Kishino & Sadao Suzuki & Ryosuke Ando & Hideshi Niimura & Hirokazu Uemura & Mikako Horita & Keizo Ohnaka & Nagato Kuriyama & Haruo Mikami & Naoyuki Takashima & Keitaro Mas, 2012. "Detailed Analysis of Japanese Population Substructure with a Focus on the Southwest Islands of Japan," PLOS ONE, Public Library of Science, vol. 7(4), pages 1-7, April.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pgen00:1000508. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosgenetics (email available below). General contact details of provider: https://journals.plos.org/plosgenetics/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.