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Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

  • 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. Feitosa
  • , Damien C. Croteau-Chonka
  • , Felix R. Day
  • , Tove Fall
  • , Teresa Ferreira
  • , Stefan Gustafsson
  • , Adam E. Locke
  • , Iain Mathieson
  • , Andre Scherag
  • Sailaja Vedantam, Andrew R. Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T. Dermitzakis, Antigone S. Dimas, Fredrik Karpe, Josine L. Min, George Nicholson, Deborah J. Clegg, Thomas Person, Jon P. Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, Amélie Bonnefond, Philippe Froguel, Jouke Jan Hottenga, Inga Prokopenko, Lindsay L. Waite, Tamara B. Harris, Albert Vernon Smith, Alan R. Shuldiner, Wendy L. McArdle, Mark J. Caulfield, Patricia B. Munroe, Henrik Grönberg, Yii Der Ida Chen, Guo Li, Jacques S. Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay Tee Khaw, Nicholas J. Wareham, Jing Hua Zhao, Najaf Amin, Ben A. Oostra, Aldi T. Kraja, Michael A. Province, L. Adrienne Cupples, Nancy L. Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S. Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H. Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A. Hicks, Åsa Johansson, Peter P. Pramstaller, Sekar Kathiresan, Elizabeth K. Speliotes, Brenda Penninx, Anna Liisa Hartikainen, Marjo Riitta Jarvelin, Ulf Gyllensten, Dorret I. Boomsma, Harry Campbell, James F. Wilson, Stephen J. Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G. Uitterlinden, Albert Hofman, M. Carola Zillikens, Martin den Heijer, Lambertus A. Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D. Spector, Caroline Hayward, Igor Rudan, Alistair S. Hall, Nilesh J. Samani, Antony Paul Attwood, Jennifer G. Sambrook, Joseph Hung, Lyle J. Palmer, Marja Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G. Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M. Nolte, Harold Snieder, Melanie M. van der Klauw, Jana V. van Vliet-Ostaptchouk, Pablo V. Gejman, Jianxin Shi, Kevin B. Jacobs, Zhaoming Wang, Stephan J.L. Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G. Martin, Sarah E. Medland, Grant W. Montgomery, Jian Yang, Daniel I. Chasman, Paul M. Ridker, Lynda M. Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G. Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P. Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R. Bornstein, Peter E.H. Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J. Swift, Matti Uusitupa, Mustafa Atalay, Timo A. Lakka, Rainer Rauramaa, Jennifer L. Bolton, Gerry Fowkes, Ross M. Fraser, Jackie F. Price, Krista Fischer, Kaarel KrjutÅkov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K. Ong, Peter S. Chines, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Sarah Edkins, Paul W. Franks, Göran Hallmans, Dmitry Shungin, Andrewvid da Morris, Colin N.A. Palmer, Raimund Erbel, Susanne Moebus, Markus M. Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E. Humphries, Rona J. Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O. Boehm, Marcus E. Kleber, Winfried März, Bernhard R. Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W.G. Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K.E. Magnusson, Nancy L. Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L. Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L. Assimes, Inês Barroso, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Caroline S. Fox, Timothy Frayling, Leif C. Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L. Mohlke, Jeffrey R. O'Connell, David Schlessinger, David P. Strachan, Kari Stefansson, Cornelia M. van Duijn, Gonçalo R. Abecasis, Mark I. McCarthy, Joel N. Hirschhorn, Lu Qi, Ruth J.F. Loos, Cecilia M. Lindgren, Kari E. North, Iris M. Heid
  • Wellcome Trust Sanger Institute
  • University of Oxford
  • University of Regensburg
  • University of Lausanne
  • Swiss Institute of Bioinformatics
  • National Institutes of Health
  • University of Michigan, Ann Arbor
  • University of North Carolina at Chapel Hill
  • Cambridge University Hospitals NHS Foundation Trust
  • University of Tartu
  • University of Tartu
  • Tulane University
  • Harvard University
  • Washington University St. Louis
  • Karolinska Institutet
  • University of Duisburg-Essen
  • Boston Children's Hospital
  • Broad Institute
  • University of Exeter
  • deCODE Genetics
  • University of Geneva
  • Alexander Fleming Biomedical Sciences Research Center
  • MRC Harwell
  • University of Texas Southwestern Medical Center
  • Institut Pasteur de Lille
  • Imperial College London
  • Vrije Universiteit Amsterdam
  • HudsonAlpha Institute for Biotechnology
  • Icelandic Heart Association
  • University of Iceland
  • University of Maryland, Baltimore
  • Department of Veterans Affairs
  • University of Bristol
  • Queen Mary University of London
  • Cedars-Sinai Medical Center
  • University of California at Los Angeles
  • University of Washington
  • University of Cambridge
  • Erasmus University Rotterdam
  • Leiden University
  • Netherlands Genomics Initiative
  • Boston University
  • National Institute for Health and Welfare
  • University of Helsinki
  • South Karelia Central Hospital
  • Hospital Universitario La Paz
  • University for Continuing Education Krems
  • South Ostrobothnia Central Hospital
  • Nordic Center of Cardiovascular Research (NCCR)
  • University of Lübeck
  • University Medical Center Schleswig-Holstein
  • German Centre for Cardiovascular Research
  • Innsbruck Medical University
  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • Ludwig Maximilian University of Munich
  • EURAC Research
  • Uppsala University
  • General Central Hospital
  • Massachusetts General Hospital
  • Massachusetts Institute of Technology
  • University of Groningen
  • University of Oulu
  • University of Edinburgh
  • VU University Medical Center
  • Radboud University Nijmegen
  • Netherlands Association of Comprehensive Cancer Centres
  • National Research Council of Italy
  • University of Greifswald
  • Leipzig University
  • King's College London
  • NHS Lothian
  • University of Leeds
  • University of Leicester
  • University Hospitals of Leicester NHS Trust
  • NHS Blood and Transplant
  • University of Western Australia
  • Sir Charles Gairdner Hospital
  • Ontario Institute for Cancer Research
  • University of Toronto
  • Helsinki University Hospital
  • University of Montreal
  • University of Gothenburg
  • University of Milan
  • The University of Chicago
  • NorthShore University HealthSystem
  • SAIC
  • Queensland Institute of Medical Research
  • Brigham and Women’s Hospital
  • Tampere University
  • University of Turku
  • Kaiser Permanente
  • Amsterdam University Medical Centers
  • University College London
  • Telethon Kids Institute
  • Queen Elizabeth II Medical Centre Trust
  • Technische Universität Dresden
  • University of Eastern Finland
  • Medical Research Council
  • Finnish Diabetes Association
  • Pirkanmaa Hospital District
  • Lund University
  • Umeå University
  • University of Dundee
  • University of Bonn
  • Norwegian University of Science and Technology
  • Hannover Medical School
  • Ulm University
  • LURIC Study Nonprofit LLC
  • Heidelberg University 
  • SYNLAB International GmbH
  • Cardiology Group
  • Université de Strasbourg
  • University of Milan - Bicocca
  • Queen's University Belfast
  • Harokopio University
  • Onassis Cardiac Surgery Center
  • University of Tromsø – The Arctic University of Norway
  • Stanford University
  • National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
  • Albert Einstein College of Medicine
  • St. George's University of London
  • Oxford University Hospitals NHS Foundation Trust
  • Icahn School of Medicine at Mount Sinai

Research output: Contribution to journalArticlepeer-review

Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10-8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Original languageEnglish
Article numbere1003500
JournalPLoS Genetics
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 2013
Externally publishedYes

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